Liu J; Zheng Y; Xiong Y; Ma R; Lin Z; Lin H; Anduar-Sanchez M; Bartkova J; Liu J; Foiani M; Bartek J; Kosar M Nucleoporin TPR integrates MAPK signaling with mitogen-induced transcriptional programs Journal Article In: Cell death and disease, vol. 17, iss. 1, pp. 400, 2026. @article{%a1.%Y_283,
title = {Nucleoporin TPR integrates MAPK signaling with mitogen-induced transcriptional programs},
author = {Liu J and Zheng Y and Xiong Y and Ma R and Lin Z and Lin H and Anduar-Sanchez M and Bartkova J and Liu J and Foiani M and Bartek J and Kosar M},
url = {https://www.nature.com/articles/s41419-026-08760-8},
doi = {10.1038/s41419-026-08760-8},
year = {2026},
date = {2026-06-16},
journal = {Cell death and disease},
volume = {17},
issue = {1},
pages = {400},
abstract = {The nuclear pore complex (NPC) component TPR has emerged as a multifunctional scaffold implicated in mitosis, chromatin organization, mRNA export, and genome stability. However, TPR's role in mitogenic signal transduction remains largely unexplored. Here, we investigate whether nucleoporin TPR functions as a MAPK-regulated nuclear component that modulates mitogenic signals initiated at the plasma membrane-including EGFR activation-and their transcriptional output. Transcriptomic profiling reveals that TPR depletion reshapes EGF-induced, MAPK-responsive gene expression, including altered expression of MAPK pathway components and enhanced induction of the immediate-early gene FOS. Functionally, TPR-depleted cells exhibit increased FOS induction upon EGF stimulation and altered EGF-driven cell-cycle progression. Using a novel phospho-specific monoclonal antibody, we show that TPR is phosphorylated at Ser2155 following EGFR activation via the canonical RAS-RAF-MEK-ERK MAPK cascade, placing TPR downstream of MAPK pathway activation. This phosphorylation is suppressed by clinically used EGFR and BRAF inhibitors and, conversely, is constitutively induced by oncogenic RAS and BRAF, indicating that Ser2155 phosphorylation reflects MAPK pathway activity. In vivo, CRISPR/Cas9-engineered Tpr haploinsufficient mice show changes in MAPK pathway regulatory gene expression in bulk spleen RNA-seq, consistent with findings in human cells, and enhanced Fos induction in splenocytes upon CD3/CD28 stimulation, together suggesting a conserved association between TPR levels and altered MAPK-related transcriptomic profiles. Finally, immunohistochemical analysis reveals elevated TPR phosphorylation in serous ovarian carcinoma and heterogeneous phosphorylation patterns in triple-negative breast cancer, two tumor types frequently characterized by MAPK pathway hyperactivation. Together, these findings uncover a previously unappreciated role for TPR as a MAPK-responsive nuclear factor and support a model in which NPC-associated components fine-tune mitogen-induced transcriptional responses.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The nuclear pore complex (NPC) component TPR has emerged as a multifunctional scaffold implicated in mitosis, chromatin organization, mRNA export, and genome stability. However, TPR's role in mitogenic signal transduction remains largely unexplored. Here, we investigate whether nucleoporin TPR functions as a MAPK-regulated nuclear component that modulates mitogenic signals initiated at the plasma membrane-including EGFR activation-and their transcriptional output. Transcriptomic profiling reveals that TPR depletion reshapes EGF-induced, MAPK-responsive gene expression, including altered expression of MAPK pathway components and enhanced induction of the immediate-early gene FOS. Functionally, TPR-depleted cells exhibit increased FOS induction upon EGF stimulation and altered EGF-driven cell-cycle progression. Using a novel phospho-specific monoclonal antibody, we show that TPR is phosphorylated at Ser2155 following EGFR activation via the canonical RAS-RAF-MEK-ERK MAPK cascade, placing TPR downstream of MAPK pathway activation. This phosphorylation is suppressed by clinically used EGFR and BRAF inhibitors and, conversely, is constitutively induced by oncogenic RAS and BRAF, indicating that Ser2155 phosphorylation reflects MAPK pathway activity. In vivo, CRISPR/Cas9-engineered Tpr haploinsufficient mice show changes in MAPK pathway regulatory gene expression in bulk spleen RNA-seq, consistent with findings in human cells, and enhanced Fos induction in splenocytes upon CD3/CD28 stimulation, together suggesting a conserved association between TPR levels and altered MAPK-related transcriptomic profiles. Finally, immunohistochemical analysis reveals elevated TPR phosphorylation in serous ovarian carcinoma and heterogeneous phosphorylation patterns in triple-negative breast cancer, two tumor types frequently characterized by MAPK pathway hyperactivation. Together, these findings uncover a previously unappreciated role for TPR as a MAPK-responsive nuclear factor and support a model in which NPC-associated components fine-tune mitogen-induced transcriptional responses. |
di Lillo A; Tavella S; Iannelli F; Crisafulli G; Gioia U; Trastus LA; Cabrini M; d'Adda di Fagagna F Site-specific DNA double-strand break induces local transcription in cis and protein expression Journal Article Forthcoming In: Communications biology, Forthcoming. @article{%a1.%Y_282,
title = {Site-specific DNA double-strand break induces local transcription in cis and protein expression},
author = {di Lillo A and Tavella S and Iannelli F and Crisafulli G and Gioia U and Trastus LA and Cabrini M and {d'Adda di Fagagna F} },
url = {https://www.nature.com/articles/s42003-026-10230-y},
doi = {10.1038/s42003-026-10230-y},
year = {2026},
date = {2026-06-16},
urldate = {2026-06-16},
journal = {Communications biology},
abstract = {The DNA damage response is a complex network of pathways that cells activate to safeguard genome integrity following DNA damage, including DNA double-strand breaks. We and others previously reported that RNA polymerase II, together with components of the preinitiation complex, is recruited to exposed DNA ends. This results in the assembly of a fully competent transcriptional apparatus and the synthesis of damage-induced long non-coding RNAs, which are necessary for full DNA damage response activation. Thus, DNA double-strand breaks could act as transcriptional promoters. Whether such DNA breaks, generated upstream of an open reading frame lacking a transcriptional promoter and followed by a polyadenylation signal, can induce the transcription of a coding RNA that is subsequently translated into a protein product remains unknown. Here, taking advantage of the CRISPR/Cas9 technology, we generate a sequence-specific double-strand break upstream of a promoter-less, and therefore silent, reporter gene in two distinct cellular systems. In both cell models, a DNA double-strand break is sufficient to trigger the expression of polyadenylated transcripts and a protein product. Collectively, our results demonstrate that DNA double-strand breaks can act as functional promoters capable of driving protein synthesis, revealing an additional mechanism through which DNA damage can regulate gene expression.},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
The DNA damage response is a complex network of pathways that cells activate to safeguard genome integrity following DNA damage, including DNA double-strand breaks. We and others previously reported that RNA polymerase II, together with components of the preinitiation complex, is recruited to exposed DNA ends. This results in the assembly of a fully competent transcriptional apparatus and the synthesis of damage-induced long non-coding RNAs, which are necessary for full DNA damage response activation. Thus, DNA double-strand breaks could act as transcriptional promoters. Whether such DNA breaks, generated upstream of an open reading frame lacking a transcriptional promoter and followed by a polyadenylation signal, can induce the transcription of a coding RNA that is subsequently translated into a protein product remains unknown. Here, taking advantage of the CRISPR/Cas9 technology, we generate a sequence-specific double-strand break upstream of a promoter-less, and therefore silent, reporter gene in two distinct cellular systems. In both cell models, a DNA double-strand break is sufficient to trigger the expression of polyadenylated transcripts and a protein product. Collectively, our results demonstrate that DNA double-strand breaks can act as functional promoters capable of driving protein synthesis, revealing an additional mechanism through which DNA damage can regulate gene expression. |
Cannone E; La Spina M; Gnutti B; Tesoriero C; Castagnaro S; Tobia C; La Via L; Sabatelli P; Faldini C; Fiume G; Vettori A; Finazzi D; Gennarelli M; Magri C; Schiavone M Integrated RNA sequencing and in vivo biosensor imaging define the early pathogenic cascade of Duchenne muscular dystrophy Journal Article Forthcoming In: Translational research, Forthcoming. @article{%a1.%Y_281,
title = {Integrated RNA sequencing and in vivo biosensor imaging define the early pathogenic cascade of Duchenne muscular dystrophy},
author = {Cannone E and La Spina M and Gnutti B and Tesoriero C and Castagnaro S and Tobia C and La Via L and Sabatelli P and Faldini C and Fiume G and Vettori A and Finazzi D and Gennarelli M and Magri C and Schiavone M},
url = {https://www.sciencedirect.com/science/article/pii/S1931524426001192?via%3Dihub},
doi = {10.1016/j.trsl.2026.06.007},
year = {2026},
date = {2026-06-16},
journal = {Translational research},
abstract = {Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by loss of dystrophin, and characterized by progressive muscle wasting, with massive replacement of muscle fibers with adipose tissue. Yet, the early molecular events that initiate pathology remain poorly defined. Here, we combined longitudinal RNA sequencing of sapje dystrophic zebrafish (a single-mutation vertebrate model of human DMD characterized by a severe phenotype), transcriptomic profiling of human DMD myoblasts and myotubes, and functional in vivo imaging using pathway-specific zebrafish biosensors to reconstruct the cascade of events triggered by dystrophin deficiency. We observed that the earliest stages of disease are characterized by marked downregulation of genes controlling cytosolic Ca2+ homeostasis, mitochondrial function and organization, and Pax3/Mef2a/Srf-mediated transcriptional programs essential for satellite cell maintenance and muscle differentiation. These early deficits precede robust but ineffective regenerative and metabolic compensatory responses, accompanied by extracellular matrix remodeling and TGFβ activation. At advanced stages, both sapje zebrafish and human DMD myotubes converge on profound mitochondrial dysfunction, impaired cell-cycle control, and chronic inflammation signaling. Live imaging of sapje zebrafish biosensors validated these transcriptomic signatures, revealing reduced Notch, Bmp, Shh, Hif-1a and Wnt signaling, along with aberrant TGFβ activity and disrupted mitochondrial dynamics in vivo. Together, these findings identify a conserved temporal sequence linking early Ca2+ dysregulation to mitochondrial failure, satellite cell hyperactivation, and fibrotic remodeling, providing mechanistic insights and therapeutic targets for early intervention in DMD patients.},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by loss of dystrophin, and characterized by progressive muscle wasting, with massive replacement of muscle fibers with adipose tissue. Yet, the early molecular events that initiate pathology remain poorly defined. Here, we combined longitudinal RNA sequencing of sapje dystrophic zebrafish (a single-mutation vertebrate model of human DMD characterized by a severe phenotype), transcriptomic profiling of human DMD myoblasts and myotubes, and functional in vivo imaging using pathway-specific zebrafish biosensors to reconstruct the cascade of events triggered by dystrophin deficiency. We observed that the earliest stages of disease are characterized by marked downregulation of genes controlling cytosolic Ca2+ homeostasis, mitochondrial function and organization, and Pax3/Mef2a/Srf-mediated transcriptional programs essential for satellite cell maintenance and muscle differentiation. These early deficits precede robust but ineffective regenerative and metabolic compensatory responses, accompanied by extracellular matrix remodeling and TGFβ activation. At advanced stages, both sapje zebrafish and human DMD myotubes converge on profound mitochondrial dysfunction, impaired cell-cycle control, and chronic inflammation signaling. Live imaging of sapje zebrafish biosensors validated these transcriptomic signatures, revealing reduced Notch, Bmp, Shh, Hif-1a and Wnt signaling, along with aberrant TGFβ activity and disrupted mitochondrial dynamics in vivo. Together, these findings identify a conserved temporal sequence linking early Ca2+ dysregulation to mitochondrial failure, satellite cell hyperactivation, and fibrotic remodeling, providing mechanistic insights and therapeutic targets for early intervention in DMD patients. |
Di Vincenzo A; Luca T; Perugini J; Lezoche G; Barresi V; De Geronimo V; Donati A; Casarotta E; Tomasello M; Pezzino S; Scuderi C; Di Cristoforo A; Pieroni A; Petrelli M; Napoli MV; Figueiredo N; Corgosinho FC; Sbarbati A; Merlini L; Sabatelli P; Graciotti L; Spadoni T; Dani C; Mattioli-Belmonte M; Condorelli DF; Gabrielli A; Malavasi F; Giordano A; Castorina S; Cinti S Role of hypertrophic adipocytes, collagen VI, and CD38 in adipose tissue fibrosis in obesity Journal Article Forthcoming In: Scientific reports, Forthcoming. @article{%a1.%Y_280,
title = {Role of hypertrophic adipocytes, collagen VI, and CD38 in adipose tissue fibrosis in obesity},
author = {Di Vincenzo A and Luca T and Perugini J and Lezoche G and Barresi V and De Geronimo V and Donati A and Casarotta E and Tomasello M and Pezzino S and Scuderi C and Di Cristoforo A and Pieroni A and Petrelli M and Napoli MV and Figueiredo N and Corgosinho FC and Sbarbati A and Merlini L and Sabatelli P and Graciotti L and Spadoni T and Dani C and Mattioli-Belmonte M and Condorelli DF and Gabrielli A and Malavasi F and Giordano A and Castorina S and Cinti S},
url = {https://www.nature.com/articles/s41598-026-49848-7},
doi = {10.1038/s41598-026-49848-7},
year = {2026},
date = {2026-05-18},
journal = {Scientific reports},
abstract = {not available},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
|
Franchini E; Bulloni M; Sorgente A; Paulikova K; Cassina L; Marafelli I; Sambri I; Pattini L; Casari G Pharmacological Restoration of Mitochondrial Permeability Transition Pore Flickering by High-Content Drug Repurposing Journal Article Forthcoming In: Pharmacological research, Forthcoming. @article{%a1.%Y_279,
title = {Pharmacological Restoration of Mitochondrial Permeability Transition Pore Flickering by High-Content Drug Repurposing},
author = {Franchini E and Bulloni M and Sorgente A and Paulikova K and Cassina L and Marafelli I and Sambri I and Pattini L and Casari G},
doi = {10.1016/j.phrs.2026.108234},
year = {2026},
date = {2026-05-18},
journal = {Pharmacological research},
abstract = {The mitochondrial permeability transition pore (mPTP) is a voltage‑ and calcium‑regulated channel located in the inner mitochondrial membrane whose activity critically influences cellular fate. While prolonged pore opening leads to mitochondrial depolarization, matrix swelling, and cell death, brief and reversible opening events, referred to as flickering, enable controlled release of calcium and reactive oxygen species and serve essential physiological functions. Emerging evidence indicates that restoring physiological mPTP flickering, rather than suppressing pore activity, may be beneficial in disorders characterized by impaired pore dynamics, including hereditary spastic paraplegia type 7 (SPG7). However, no approved therapies are currently available to promote controlled mPTP pore opening. To identify pharmacological modulators of flickering, we performed a high-content screening of 2,000 FDA and EMA-approved compounds using a validated fluorescence-based assay coupled with automated image analysis. Thirteen compounds increased both the frequency and the area of flickering events while preserving cellular and mitochondrial integrity. Validation in fibroblasts derived from SPG7 patient cells and healthy control confirmed reproducible activity across distinct genetic backgrounds. Among the prioritized candidates, berberine emerged as the most robust modulator, consistently enhancing mPTP flickering independently of SPG7 mutation status. Notably, berberine selectively increased the proportion of small-size flickering events, indicative of physiological pore activity. These findings identify berberine as a promising modulator of mPTP dynamics and support pharmacological restoration of physiological flickering as a potential therapeutic strategy for SPG7 and other disorders associated with impaired mitochondrial permeability transition pore regulation.},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
The mitochondrial permeability transition pore (mPTP) is a voltage‑ and calcium‑regulated channel located in the inner mitochondrial membrane whose activity critically influences cellular fate. While prolonged pore opening leads to mitochondrial depolarization, matrix swelling, and cell death, brief and reversible opening events, referred to as flickering, enable controlled release of calcium and reactive oxygen species and serve essential physiological functions. Emerging evidence indicates that restoring physiological mPTP flickering, rather than suppressing pore activity, may be beneficial in disorders characterized by impaired pore dynamics, including hereditary spastic paraplegia type 7 (SPG7). However, no approved therapies are currently available to promote controlled mPTP pore opening. To identify pharmacological modulators of flickering, we performed a high-content screening of 2,000 FDA and EMA-approved compounds using a validated fluorescence-based assay coupled with automated image analysis. Thirteen compounds increased both the frequency and the area of flickering events while preserving cellular and mitochondrial integrity. Validation in fibroblasts derived from SPG7 patient cells and healthy control confirmed reproducible activity across distinct genetic backgrounds. Among the prioritized candidates, berberine emerged as the most robust modulator, consistently enhancing mPTP flickering independently of SPG7 mutation status. Notably, berberine selectively increased the proportion of small-size flickering events, indicative of physiological pore activity. These findings identify berberine as a promising modulator of mPTP dynamics and support pharmacological restoration of physiological flickering as a potential therapeutic strategy for SPG7 and other disorders associated with impaired mitochondrial permeability transition pore regulation. |
Berrino E; Bellomo SE; Aquilano MC; Falcinelli M; Chesta A; Valtorta E; Zampieri D; Mauri G; Sala G; Marsoni S; Bardelli A; Sartore-Bianchi A; Siena S; Sapino A; Bonoldi E; d'Adda di Fagagna F; Marchiò C Degrees of H2AX phosphorylation correlate with unique features of the intratumoral immune microenvironment in colorectal carcinomas Journal Article In: Oncologist, vol. 31, iss. 5, 2026. @article{%a1.%Y_278,
title = {Degrees of H2AX phosphorylation correlate with unique features of the intratumoral immune microenvironment in colorectal carcinomas},
author = {Berrino E and Bellomo SE and Aquilano MC and Falcinelli M and Chesta A and Valtorta E and Zampieri D and Mauri G and Sala G and Marsoni S and Bardelli A and Sartore-Bianchi A and Siena S and Sapino A and Bonoldi E and {d'Adda di Fagagna F} and Marchiò C},
url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC13071407/},
doi = {Oncologist},
year = {2026},
date = {2026-05-18},
journal = {Oncologist},
volume = {31},
issue = {5},
abstract = {Background: The phosphorylated form of the histone H2AX (γH2AX), a sensor of DNA double-strand breaks (DSB), can serve as a biomarker of DNA damage and therapy response. This study aimed to evaluate the association between γH2AX expression and pathological, molecular, and immune features in colorectal cancer (CRC). Patients and methods: Levels of γH2AX were assessed by immunohistochemistry in a cohort of 198 CRCs, alongside immune-related markers (CD3 and CD8). A sub-cohort of 65 CRCs (26 γH2AX- and 39 γH2AX+) underwent RNA extraction and gene expression profiling using the IO360 Nanostring Panel to infer immune cell composition. Overall survival data were analyzed for exploratory correlations. Results: γH2AX+ CRCs (155/198, 78%) were significantly associated with higher stage and tumor grade (P < .01). A lower γH2AX prevalence was found in MMR-deficient tumors (64%) compared to MMR-proficient cases (81%, P = .05). γH2AX+ tumors showed increased CD3+ cell infiltration in the overall population (P = .038) and in MMR-proficient CRCs (P = .028). Gene expression analysis revealed higher T-cell counts (P < .01) and reduced B-cell abundance (P < .01) in γH2AX+ CRCs. Unsupervised clustering identified 3 immune subgroups with differential γH2AX accumulation. Cluster #3, enriched in γH2AX+ tumors, displayed increased CD8+ T-cells and conferred the best survival outcome. Conclusion: Elevated γH2AX expression correlates with MMR proficiency, aggressive histopathologic features, and a distinctive immune-active microenvironment in CRC. These findings may support γH2AX as a marker of immune-modulated CRC subgroups with potential prognostic and therapeutic relevance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: The phosphorylated form of the histone H2AX (γH2AX), a sensor of DNA double-strand breaks (DSB), can serve as a biomarker of DNA damage and therapy response. This study aimed to evaluate the association between γH2AX expression and pathological, molecular, and immune features in colorectal cancer (CRC). Patients and methods: Levels of γH2AX were assessed by immunohistochemistry in a cohort of 198 CRCs, alongside immune-related markers (CD3 and CD8). A sub-cohort of 65 CRCs (26 γH2AX- and 39 γH2AX+) underwent RNA extraction and gene expression profiling using the IO360 Nanostring Panel to infer immune cell composition. Overall survival data were analyzed for exploratory correlations. Results: γH2AX+ CRCs (155/198, 78%) were significantly associated with higher stage and tumor grade (P < .01). A lower γH2AX prevalence was found in MMR-deficient tumors (64%) compared to MMR-proficient cases (81%, P = .05). γH2AX+ tumors showed increased CD3+ cell infiltration in the overall population (P = .038) and in MMR-proficient CRCs (P = .028). Gene expression analysis revealed higher T-cell counts (P < .01) and reduced B-cell abundance (P < .01) in γH2AX+ CRCs. Unsupervised clustering identified 3 immune subgroups with differential γH2AX accumulation. Cluster #3, enriched in γH2AX+ tumors, displayed increased CD8+ T-cells and conferred the best survival outcome. Conclusion: Elevated γH2AX expression correlates with MMR proficiency, aggressive histopathologic features, and a distinctive immune-active microenvironment in CRC. These findings may support γH2AX as a marker of immune-modulated CRC subgroups with potential prognostic and therapeutic relevance. |
Palamidessi A; Frittoli E; Corada M; Martini E; Barzaghi L; Milanese C; Beznoussenko GV; Lazzarin A; Bellini EN; Mironov AA; Lavagnino Z; Magni S; Barozzi S; Parazzoli D; Tizzoni L; Dall'Olio V; Cancila V; Romani P; Di Bona M; Zobalova R; Boukalova S; Rediti M; Mastroberardino PG; Neuzil J; Foiani M; Dupont S; Tripodo C; Scita G Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA-dependent immunity in breast cancer Journal Article Forthcoming In: Nature communications, Forthcoming. @article{%a1.%Y_277,
title = {Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA-dependent immunity in breast cancer},
author = {Palamidessi A and Frittoli E and Corada M and Martini E and Barzaghi L and Milanese C and Beznoussenko GV and Lazzarin A and Bellini EN and Mironov AA and Lavagnino Z and Magni S and Barozzi S and Parazzoli D and Tizzoni L and Dall'Olio V and Cancila V and Romani P and Di Bona M and Zobalova R and Boukalova S and Rediti M and Mastroberardino PG and Neuzil J and Foiani M and Dupont S and Tripodo C and Scita G},
url = {https://www.nature.com/articles/s41467-026-71795-0},
doi = {10.1038/s41467-026-71795-0},
year = {2026},
date = {2026-05-18},
journal = {Nature communications},
abstract = {Why some tumors respond to immunotherapy ("hot" tumors) while others remain resistant ("cold" tumors) is a central challenge in oncology. Elevated RAB5A-dependent endocytosis drives tissue fluidization during the transition to invasive breast carcinoma, but its immunological consequences are unclear. Here we show that RAB5A-driven fluidization induces a mechano-metabolic stress response that disrupts the AMPK-AKAP1-DRP1 mitochondrial fission pathway, causing mitochondrial elongation. RAB5A vesicles interact with hyperfused mitochondria and promote BAX/BAK-dependent pore formation, leading to limited mitochondrial outer membrane permeabilization. This sub-lethal event is amplified by palmitoylated GASDERMIN A oligomerization on mitochondria, establishing a positive feedback loop. The resulting release of mitochondrial DNA activates the cGAS-STING innate immune pathway and drives a hyperinflammatory state. Consequently, RAB5A-expressing tumors in immunocompetent mice grow more slowly, show increased immune infiltration, and display enhanced sensitivity to immune-checkpoint blockade in a BAX/BAK-, cGAS/STING-, and mtDNA-dependent manner. These findings connect mechanical stress, mitochondrial dynamics, and innate immunity, revealing strategies to potentiate antitumor immunotherapy.},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
Why some tumors respond to immunotherapy ("hot" tumors) while others remain resistant ("cold" tumors) is a central challenge in oncology. Elevated RAB5A-dependent endocytosis drives tissue fluidization during the transition to invasive breast carcinoma, but its immunological consequences are unclear. Here we show that RAB5A-driven fluidization induces a mechano-metabolic stress response that disrupts the AMPK-AKAP1-DRP1 mitochondrial fission pathway, causing mitochondrial elongation. RAB5A vesicles interact with hyperfused mitochondria and promote BAX/BAK-dependent pore formation, leading to limited mitochondrial outer membrane permeabilization. This sub-lethal event is amplified by palmitoylated GASDERMIN A oligomerization on mitochondria, establishing a positive feedback loop. The resulting release of mitochondrial DNA activates the cGAS-STING innate immune pathway and drives a hyperinflammatory state. Consequently, RAB5A-expressing tumors in immunocompetent mice grow more slowly, show increased immune infiltration, and display enhanced sensitivity to immune-checkpoint blockade in a BAX/BAK-, cGAS/STING-, and mtDNA-dependent manner. These findings connect mechanical stress, mitochondrial dynamics, and innate immunity, revealing strategies to potentiate antitumor immunotherapy. |
Wutz G; Davidson IF; Banigan EJ; Stocsits RR; Kawasumi R; Tang W; Nagasaka K; Costantino L; Jansen R; Hirota K; Branzei D; Mirny LA; Peters JM PDS5 proteins control genome architecture by limiting the lifetime of cohesin-NIPBL complexes Journal Article In: Molecular cell, vol. 86, iss. 9, pp. 1614-1634, 2026. @article{%a1.%Y_276,
title = {PDS5 proteins control genome architecture by limiting the lifetime of cohesin-NIPBL complexes},
author = {Wutz G and Davidson IF and Banigan EJ and Stocsits RR and Kawasumi R and Tang W and Nagasaka K and Costantino L and Jansen R and Hirota K and Branzei D and Mirny LA and Peters JM},
url = {https://www.sciencedirect.com/science/article/pii/S1097276526002017?via%3Dihub},
doi = {10.1016/j.molcel.2026.03.025},
year = {2026},
date = {2026-05-18},
journal = {Molecular cell},
volume = {86},
issue = {9},
pages = {1614-1634},
abstract = {Cohesin-NIPBL complexes extrude genomic DNA into loops that are constrained by CTCF boundaries. This process has important regulatory functions and weakens the separation between euchromatic and heterochromatic compartments. Cohesin can also bind PDS5 proteins, which do not support loop extrusion but are required for the formation of CTCF boundaries. How PDS5 proteins perform this function is unknown. Here we show, by in vitro single-molecule imaging, that human PDS5 proteins stop loop extrusion by facilitating the dissociation of NIPBL from cohesin. Hi-C experiments suggest that this function is required for the establishment of CTCF boundaries in cells. In silico modeling indicates that PDS5 proteins enable the separation between compartments by limiting cohesin's velocity and chromatin residence time. The degree of this compartmentalization depends on the frequency with which chromatin is extruded relative to the time it takes for compartments to form. These results identify PDS5 proteins as key regulators of genome organization.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cohesin-NIPBL complexes extrude genomic DNA into loops that are constrained by CTCF boundaries. This process has important regulatory functions and weakens the separation between euchromatic and heterochromatic compartments. Cohesin can also bind PDS5 proteins, which do not support loop extrusion but are required for the formation of CTCF boundaries. How PDS5 proteins perform this function is unknown. Here we show, by in vitro single-molecule imaging, that human PDS5 proteins stop loop extrusion by facilitating the dissociation of NIPBL from cohesin. Hi-C experiments suggest that this function is required for the establishment of CTCF boundaries in cells. In silico modeling indicates that PDS5 proteins enable the separation between compartments by limiting cohesin's velocity and chromatin residence time. The degree of this compartmentalization depends on the frequency with which chromatin is extruded relative to the time it takes for compartments to form. These results identify PDS5 proteins as key regulators of genome organization. |
Cardano M; Cazzalini O; Maraventano G; Stivala LA; Zannini L; Prosperi E Stability of c-Myc Protein in Early S Phase Is Regulated by the Interaction with PCNA Journal Article In: International journal of molecular sciences, vol. 27, iss. 6, 2026. @article{%a1.%Y_275,
title = {Stability of c-Myc Protein in Early S Phase Is Regulated by the Interaction with PCNA},
author = {Cardano M and Cazzalini O and Maraventano G and Stivala LA and Zannini L and Prosperi E},
url = {https://www.mdpi.com/1422-0067/27/6/2745},
doi = {10.3390/ijms27062745},
year = {2026},
date = {2026-05-18},
journal = {International journal of molecular sciences},
volume = {27},
issue = {6},
abstract = {The transcription factor c-Myc is known to regulate DNA replication via a non-transcriptional mechanism by interacting with proteins of the pre-replicative complex. In addition, c-Myc localizes to DNA replication foci, similarly to Proliferating Cell Nuclear Antigen (PCNA); however, the significance of this localization remains unclear. Here, we investigated whether c-Myc interacts with PCNA and analyzed the possible function of this association. We found a conserved interaction motif, the PCNA-interacting protein (PIP) box, in the N-terminal region of c-Myc. Confocal microscopy analysis showed co-localization with PCNA in early S-phase, but not in late S-phase cells. Co-immunoprecipitation from cell extracts and pull-down of recombinant proteins indicated a direct physical association between c-Myc and PCNA, which was confirmed in situ by the Proximity Ligation Assay (PLA). Further experiments demonstrated that c-Myc interacts with CUL4A and DDB1, components of the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex, in which PCNA functions as a cofactor. Mutations in the PIP box of c-Myc, as well as depletion of CUL4A by RNA interference, resulted in an increased stability of c-Myc protein. These results suggest that the interaction with PCNA functionally contributes to the regulation of c-Myc stability in early S phase via the CRL4 complex.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The transcription factor c-Myc is known to regulate DNA replication via a non-transcriptional mechanism by interacting with proteins of the pre-replicative complex. In addition, c-Myc localizes to DNA replication foci, similarly to Proliferating Cell Nuclear Antigen (PCNA); however, the significance of this localization remains unclear. Here, we investigated whether c-Myc interacts with PCNA and analyzed the possible function of this association. We found a conserved interaction motif, the PCNA-interacting protein (PIP) box, in the N-terminal region of c-Myc. Confocal microscopy analysis showed co-localization with PCNA in early S-phase, but not in late S-phase cells. Co-immunoprecipitation from cell extracts and pull-down of recombinant proteins indicated a direct physical association between c-Myc and PCNA, which was confirmed in situ by the Proximity Ligation Assay (PLA). Further experiments demonstrated that c-Myc interacts with CUL4A and DDB1, components of the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex, in which PCNA functions as a cofactor. Mutations in the PIP box of c-Myc, as well as depletion of CUL4A by RNA interference, resulted in an increased stability of c-Myc protein. These results suggest that the interaction with PCNA functionally contributes to the regulation of c-Myc stability in early S phase via the CRL4 complex. |
Naddeo M; Roncarati R; De Felice F; Zuin E; Pace I; Iannotta F; Laprovitera N; Fontana B; Durante G; Salamon I; Storci G; De Matteis S; Ricci F; Bertuccio SN; Messelodi D; Ursi M; Roberto M; Barbato F; Ardizzoia F; Tomassini E; Sinigaglia B; Zazzeroni L; Dan E; Duardo RC; Vaglio F; Tassoni M; Pellegrini C; Gentilini M; Maffini E; Casadei B; Sales G; Zinzani PL; Bonafe’ M; Ferracin M; Bonifazi F Pre-treatment circulating microRNA signatures predict outcomes of anti-CD19 CAR T-cell therapy Journal Article Forthcoming In: Haematologica, Forthcoming. @article{%a1.%Y_274,
title = {Pre-treatment circulating microRNA signatures predict outcomes of anti-CD19 CAR T-cell therapy},
author = {Naddeo M and Roncarati R and De Felice F and Zuin E and Pace I and Iannotta F and Laprovitera N and Fontana B and Durante G and Salamon I and Storci G and De Matteis S and Ricci F and Bertuccio SN and Messelodi D and Ursi M and Roberto M and Barbato F and Ardizzoia F and Tomassini E and Sinigaglia B and Zazzeroni L and Dan E and Duardo RC and Vaglio F and Tassoni M and Pellegrini C and Gentilini M and Maffini E and Casadei B and Sales G and Zinzani PL and Bonafe’ M and Ferracin M and Bonifazi F},
url = {https://haematologica.org/article/view/14143},
doi = {10.3324/haematol.2025.300294},
year = {2026},
date = {2026-05-18},
journal = {Haematologica},
abstract = {not available},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
|
Calcaterra V; Cena H; Biino G; Scavone IAM; Vincenti A; Zuccotti G Validation of an enhanced pediatric vitamin D deficiency score incorporating sun exposure timing and BMI z-score: analysis in a combined cohort of children Journal Article In: European journal of pediatrics, vol. 185, iss. 4, pp. 226, 2026. @article{%a1.%Y_273,
title = {Validation of an enhanced pediatric vitamin D deficiency score incorporating sun exposure timing and BMI z-score: analysis in a combined cohort of children},
author = {Calcaterra V and Cena H and Biino G and Scavone IAM and Vincenti A and Zuccotti G},
url = {https://link.springer.com/article/10.1007/s00431-026-06890-x},
doi = {10.1007/s00431-026-06890-x},
year = {2026},
date = {2026-05-18},
journal = {European journal of pediatrics},
volume = {185},
issue = {4},
pages = {226},
abstract = {Early identification of vitamin D (VitD) deficiency in childhood is essential to support timely prevention and intervention strategies. Building on the previously validated pediatric EVIDENCe-Q questionnaire, this study aimed to refine the tool by integrating two patient-specific weighted variables, sun exposure during peak UVB hours, and BMI z-score categories, both recognized determinants of circulating 25-hydroxyvitamin D (25-OH-D) levels. A total of 354 children (190F/164 M) completed a 20-item pediatric VitD risk questionnaire. Serum 25-OH-D concentrations were available for 280 participants. Three scoring algorithms were evaluated: the unweighted standard model, the sun-weighted model, and the sun + BMI-weighted model. Statistical analyses included ANOVA, Pearson correlations, and receiver operating characteristic (ROC) analyses across biochemical thresholds of vitamin D deficiency and insufficiency (< 10, < 20, and < 30 ng/mL). Vitamin D deficiency (< 10 ng/mL) was observed in 6.8% of participants, while insufficiency affected 38.1% (< 20 ng/mL) and 74.7% (< 30 ng/mL). The unweighted standard model did not discriminate among vitamin D categories (p = 0.622). In contrast, both weighted models showed significant discrimination (sun-weighted: p = 0.036; sun + BMI-weighted: p = 0.030). Only the sun + BMI-weighted model was significantly correlated with serum 25-OH-D levels (r = - 0.13; p = 0.023). ROC analyses demonstrated limited accuracy for the unweighted model, whereas the weighted models showed moderate discriminatory ability, with the Sun + BMI-Weighted Model providing the strongest overall performance.
Conclusions: Incorporating weighted patient-specific variables improves the discriminatory capacity of the pediatric EVIDENCe-Q. Despite moderate accuracy, particularly at lower thresholds, the refined questionnaire, especially the sun + BMI-weighted version, represents a practical, noninvasive screening tool to identify children at risk of hypovitaminosis D.
What is known: • Vitamin D deficiency is highly prevalent in children worldwide, even in sun-rich regions, and is influenced by factors such as sun exposure and adiposity. • Serum 25-OH-D measurement is the diagnostic gold standard, while questionnaire-based tools offer a non-invasive but currently less accurate alternative in pediatrics.
What is new: • Incorporating weighted factors for peak UVB sun exposure and BMI z-score signifi cantly improves the predictive performance of the pediatric EVIDENCe-Q. • The Sun + BMI-weighted model shows a significant correlation with serum 25-OH-D and enhances identification of children at risk of hypovitaminosis D (30 ng/mL).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Early identification of vitamin D (VitD) deficiency in childhood is essential to support timely prevention and intervention strategies. Building on the previously validated pediatric EVIDENCe-Q questionnaire, this study aimed to refine the tool by integrating two patient-specific weighted variables, sun exposure during peak UVB hours, and BMI z-score categories, both recognized determinants of circulating 25-hydroxyvitamin D (25-OH-D) levels. A total of 354 children (190F/164 M) completed a 20-item pediatric VitD risk questionnaire. Serum 25-OH-D concentrations were available for 280 participants. Three scoring algorithms were evaluated: the unweighted standard model, the sun-weighted model, and the sun + BMI-weighted model. Statistical analyses included ANOVA, Pearson correlations, and receiver operating characteristic (ROC) analyses across biochemical thresholds of vitamin D deficiency and insufficiency (< 10, < 20, and < 30 ng/mL). Vitamin D deficiency (< 10 ng/mL) was observed in 6.8% of participants, while insufficiency affected 38.1% (< 20 ng/mL) and 74.7% (< 30 ng/mL). The unweighted standard model did not discriminate among vitamin D categories (p = 0.622). In contrast, both weighted models showed significant discrimination (sun-weighted: p = 0.036; sun + BMI-weighted: p = 0.030). Only the sun + BMI-weighted model was significantly correlated with serum 25-OH-D levels (r = - 0.13; p = 0.023). ROC analyses demonstrated limited accuracy for the unweighted model, whereas the weighted models showed moderate discriminatory ability, with the Sun + BMI-Weighted Model providing the strongest overall performance.
Conclusions: Incorporating weighted patient-specific variables improves the discriminatory capacity of the pediatric EVIDENCe-Q. Despite moderate accuracy, particularly at lower thresholds, the refined questionnaire, especially the sun + BMI-weighted version, represents a practical, noninvasive screening tool to identify children at risk of hypovitaminosis D.
What is known: • Vitamin D deficiency is highly prevalent in children worldwide, even in sun-rich regions, and is influenced by factors such as sun exposure and adiposity. • Serum 25-OH-D measurement is the diagnostic gold standard, while questionnaire-based tools offer a non-invasive but currently less accurate alternative in pediatrics.
What is new: • Incorporating weighted factors for peak UVB sun exposure and BMI z-score signifi cantly improves the predictive performance of the pediatric EVIDENCe-Q. • The Sun + BMI-weighted model shows a significant correlation with serum 25-OH-D and enhances identification of children at risk of hypovitaminosis D (30 ng/mL). |
Scolari F; Perez-Staples D Editorial Overview: Integrating behaviour, ecology, and technology in contemporary insect science Journal Article In: Current opinion in insect science, pp. 101537, 2026. @article{%a1.%Y,
title = {Editorial Overview: Integrating behaviour, ecology, and technology in contemporary insect science},
author = {Scolari F and Perez-Staples D},
url = {https://www.sciencedirect.com/science/article/pii/S2214574526000532?via%3Dihub},
doi = {10.1016/j.cois.2026.101537},
year = {2026},
date = {2026-05-18},
urldate = {2026-05-18},
journal = {Current opinion in insect science},
pages = {101537},
abstract = {not available},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Mattioli E; Cenni V; Sabatelli P; Schena E; Santi S; Fiorillo C; Bruno C; Pini A; Giannotta M; Cavallo M; Errani C; Cattin E; Benati D; Recchia A; Lattanzi G Emerin is necessary for microtubule-organizing center translocation to the nuclear envelope of muscle cells Journal Article Forthcoming In: Cell death and disease, Forthcoming. @article{%a1.%Y_271,
title = {Emerin is necessary for microtubule-organizing center translocation to the nuclear envelope of muscle cells},
author = {Mattioli E and Cenni V and Sabatelli P and Schena E and Santi S and Fiorillo C and Bruno C and Pini A and Giannotta M and Cavallo M and Errani C and Cattin E and Benati D and Recchia A and Lattanzi G},
url = {https://www.nature.com/articles/s41419-026-08819-6},
doi = {10.1038/s41419-026-08819-6},
year = {2026},
date = {2026-05-18},
journal = {Cell death and disease},
abstract = {During myogenic differentiation, the Microtubule-Organizing Center (MTOC) is relocated to the nuclear envelope by a molecular platform including Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins, A Kinase Anchoring Proteins (AKAP9 and AKAP6) and Pericentriolar Material 1 (PCM-1). Here, we show that emerin is required for centrosomal protein recruitment to the nuclear periphery of myonuclei and microtubule dynamics. In fact, in type 1 Emery-Dreifuss Muscular Dystrophy (EDMD1), loss of emerin was associated with altered pericentrin recruitment to the nuclear envelope, LINC protein impairment at the nuclear poles of myonuclei and microtubule organization defects. As a consequence, dynein, mitochondrial distribution and nuclear alignment along the longitudinal axis of the myotubes were altered in EDMD1 myotubes. Moreover, reduced levels of AKAP6 and PKA were detected at the nuclear periphery of EDMD1 myotubes, possibly contributing to an aberrant nuclear localization of the mechanosensing factor YAP. Upon rescue of emerin expression by CRISPR correction of mutated EMD gene: SUN1/2, pericentrin, AKAP6 and PKA were restored at the nuclear envelope and a correct YAP localization was observed in EDMD1 muscle cells. These results show that emerin is required for Nuclear Envelope-MTOC (NE-MTOC) organization in differentiating skeletal muscle cells and suggest that disruption of such complex is a key pathogenetic event in Emery-Dreifuss Muscular Dystrophy.},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
During myogenic differentiation, the Microtubule-Organizing Center (MTOC) is relocated to the nuclear envelope by a molecular platform including Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins, A Kinase Anchoring Proteins (AKAP9 and AKAP6) and Pericentriolar Material 1 (PCM-1). Here, we show that emerin is required for centrosomal protein recruitment to the nuclear periphery of myonuclei and microtubule dynamics. In fact, in type 1 Emery-Dreifuss Muscular Dystrophy (EDMD1), loss of emerin was associated with altered pericentrin recruitment to the nuclear envelope, LINC protein impairment at the nuclear poles of myonuclei and microtubule organization defects. As a consequence, dynein, mitochondrial distribution and nuclear alignment along the longitudinal axis of the myotubes were altered in EDMD1 myotubes. Moreover, reduced levels of AKAP6 and PKA were detected at the nuclear periphery of EDMD1 myotubes, possibly contributing to an aberrant nuclear localization of the mechanosensing factor YAP. Upon rescue of emerin expression by CRISPR correction of mutated EMD gene: SUN1/2, pericentrin, AKAP6 and PKA were restored at the nuclear envelope and a correct YAP localization was observed in EDMD1 muscle cells. These results show that emerin is required for Nuclear Envelope-MTOC (NE-MTOC) organization in differentiating skeletal muscle cells and suggest that disruption of such complex is a key pathogenetic event in Emery-Dreifuss Muscular Dystrophy. |
Vinciguerra M; El Kharef C; Bruhn C; Falbo L; Milanese C; Audano M; Beznoussenko GV; Mironov AA; Delia D; Foiani M; Mastroberardino PG; Mitro N; Costanzo V Targeting the FNIP2-SERCA2b axis improves metabolic and mitochondrial defects in Ataxia Telangiectasia Journal Article In: Cell death & disease, vol. 17, iss. 1, pp. 290, 2026. @article{%a1.%Y_270,
title = {Targeting the FNIP2-SERCA2b axis improves metabolic and mitochondrial defects in Ataxia Telangiectasia},
author = {Vinciguerra M and El Kharef C and Bruhn C and Falbo L and Milanese C and Audano M and Beznoussenko GV and Mironov AA and Delia D and Foiani M and Mastroberardino PG and Mitro N and Costanzo V},
url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC13031930/},
doi = {10.1038/s41419-026-08507-5},
year = {2026},
date = {2026-05-18},
journal = {Cell death & disease},
volume = {17},
issue = {1},
pages = {290},
abstract = {Ataxia telangiectasia (AT) is a rare multisystem disorder caused by the loss of functional ATM protein, leading to immunodeficiency, cancer predisposition, neurodegeneration, diabetes, heart failure, and premature aging. Although ATM's role as a sensor of DNA double-strand breaks (DSBs) is well established, the mechanisms underlying the diverse AT phenotypes remain incompletely understood, with evidence suggesting they extend beyond DSB sensing. Here, we uncover widespread glycogen accumulation as a key feature of AT cells and tissues, driven by dysregulated glucose metabolism and impaired mitochondrial respiration assessed with a multidimensional approach including metabolomics, flux analysis, histopathology, bioenergetic measurements, and electron tomography. These metabolic defects contribute to reduced cellular viability and premature senescence observed in AT patient-derived cells. Strikingly, inactivation of FNIP2, which controls mitochondrial respiration, partially rescues these defects in AT cellular models. We show that FNIP2 interacts with the SERCA2b calcium channel, and its inactivation enhances cytoplasmic calcium availability, stimulating mitochondrial respiration and increasing glucose consumption. This metabolic reprogramming prevents glycogen accumulation and improves survival in AT primary cells. Our findings provide novel insights into AT pathophysiology and indicate the FNIP2-SERCA2b axis as a novel potential target for mitigating the systemic effects of AT and improving outcomes in this complex disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Ataxia telangiectasia (AT) is a rare multisystem disorder caused by the loss of functional ATM protein, leading to immunodeficiency, cancer predisposition, neurodegeneration, diabetes, heart failure, and premature aging. Although ATM's role as a sensor of DNA double-strand breaks (DSBs) is well established, the mechanisms underlying the diverse AT phenotypes remain incompletely understood, with evidence suggesting they extend beyond DSB sensing. Here, we uncover widespread glycogen accumulation as a key feature of AT cells and tissues, driven by dysregulated glucose metabolism and impaired mitochondrial respiration assessed with a multidimensional approach including metabolomics, flux analysis, histopathology, bioenergetic measurements, and electron tomography. These metabolic defects contribute to reduced cellular viability and premature senescence observed in AT patient-derived cells. Strikingly, inactivation of FNIP2, which controls mitochondrial respiration, partially rescues these defects in AT cellular models. We show that FNIP2 interacts with the SERCA2b calcium channel, and its inactivation enhances cytoplasmic calcium availability, stimulating mitochondrial respiration and increasing glucose consumption. This metabolic reprogramming prevents glycogen accumulation and improves survival in AT primary cells. Our findings provide novel insights into AT pathophysiology and indicate the FNIP2-SERCA2b axis as a novel potential target for mitigating the systemic effects of AT and improving outcomes in this complex disease. |
Modafferi S; Silenzi V; Garbelli A; Lazoi G; Scarian E; D'Uva S; Santini T; Riccardi A; Cozzolino M; Pansarasa O; D'Ambrosi N; Sabbioneda S; Morlando M; Francia S Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems Journal Article Forthcoming In: Cell death & disease, Forthcoming. @article{%a1.%Y_269,
title = {Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems},
author = {Modafferi S and Silenzi V and Garbelli A and Lazoi G and Scarian E and D'Uva S and Santini T and Riccardi A and Cozzolino M and Pansarasa O and D'Ambrosi N and Sabbioneda S and Morlando M and Francia S},
url = {https://www.nature.com/articles/s41419-026-08603-6},
doi = {10.1038/s41419-026-08603-6},
year = {2026},
date = {2026-05-18},
journal = {Cell death & disease},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterised by the aggregation of TDP-43 and mutant FUS in the cytoplasm of affected motor neurons. Accumulation of DNA damage is emerging as a novel correlative trait of ALS. We recently showed that formation of TDP-43 and FUS cytoplasmic inclusions (CIs) lead to DNA damage accumulation through dysregulation of the DNA damage response (DDR). However, the multiple molecular mechanisms contributing to DNA damage accumulation in affected motor neurons in ALS have not been fully elucidated. In recent years, chemical inhibition of the serine/threonine kinase CHK1 was shown to lead to accumulation of DNA breaks as well as increased apoptosis, in differentiated cortical neurons. Notably, CHK1 has been involved in DNA double-strand break repair in non-dividing cells, by acting through the histone chaperone ASF1A. In this article, we show that cells bearing FUS and TDP-43 CIs show downregulation of the protein levels of CHK1 and ASF1A. We observe CHK1 protein downregulation in neuronal cell lines, as well as in patient-derived motor neurons progenitors and in the spinal cord of a FUS-ALS mouse model. Restoration of the nuclear levels of CHK1 and ASF1A via transient overexpression, is sufficient to reduce DNA damage signal accumulation and rescues DDR defects. Importantly, we show that the ubiquitin-proteasome pathway is responsible for CHK1 degradation in cells bearing FUS CI, since its inhibition restores CHK1 and ASF1A protein levels. Our study demonstrates that proteasomal-dependent CHK1 and ASF1A downregulation contributes to accumulation of DNA damage in cells affected by ALS-linked protein aggregates.},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
Amyotrophic lateral sclerosis (ALS) is characterised by the aggregation of TDP-43 and mutant FUS in the cytoplasm of affected motor neurons. Accumulation of DNA damage is emerging as a novel correlative trait of ALS. We recently showed that formation of TDP-43 and FUS cytoplasmic inclusions (CIs) lead to DNA damage accumulation through dysregulation of the DNA damage response (DDR). However, the multiple molecular mechanisms contributing to DNA damage accumulation in affected motor neurons in ALS have not been fully elucidated. In recent years, chemical inhibition of the serine/threonine kinase CHK1 was shown to lead to accumulation of DNA breaks as well as increased apoptosis, in differentiated cortical neurons. Notably, CHK1 has been involved in DNA double-strand break repair in non-dividing cells, by acting through the histone chaperone ASF1A. In this article, we show that cells bearing FUS and TDP-43 CIs show downregulation of the protein levels of CHK1 and ASF1A. We observe CHK1 protein downregulation in neuronal cell lines, as well as in patient-derived motor neurons progenitors and in the spinal cord of a FUS-ALS mouse model. Restoration of the nuclear levels of CHK1 and ASF1A via transient overexpression, is sufficient to reduce DNA damage signal accumulation and rescues DDR defects. Importantly, we show that the ubiquitin-proteasome pathway is responsible for CHK1 degradation in cells bearing FUS CI, since its inhibition restores CHK1 and ASF1A protein levels. Our study demonstrates that proteasomal-dependent CHK1 and ASF1A downregulation contributes to accumulation of DNA damage in cells affected by ALS-linked protein aggregates. |
Bonenti E; Cardano M; Buscemi G; Zannini L TSPY-like 2, Beyond the Histone Chaperone Role Journal Article In: Biomolecules, vol. 16, iss. 3, pp. 378, 2026. @article{%a1.%Y_268,
title = {TSPY-like 2, Beyond the Histone Chaperone Role},
author = {Bonenti E and Cardano M and Buscemi G and Zannini L},
url = {https://www.mdpi.com/2218-273X/16/3/378},
doi = {10.3390/biom16030378},
year = {2026},
date = {2026-05-18},
journal = {Biomolecules},
volume = {16},
issue = {3},
pages = {378},
abstract = {Chromatin is a dynamic cellular structure basically constituted by nucleosomes, which consist of a DNA sequence wrapped around an octameric histones core. Histone synthesis and transport, nucleosome formation and proper chromatin assembly is an ordered and stepwise process guided by histone chaperones. Several families of histone chaperones have been identified and one of them is the nucleosome assembly protein (NAP) superfamily. Members of this family have been involved not only in chromatin constitution and regulation but also in several other cellular processes, such as nucleocytoplasmic shuttling, DNA replication, transcription and cell-cycle regulation. Testis specific protein Y-like 2 (TSPYL2) is a peculiar member of the NAP superfamily of histone chaperone. This protein has been initially isolated as a nuclear antigen in patients affected by discoid lupus erythematosus and as a TGF-β target. Its ability to bind histones has been demonstrated. In addition, TSPYL2 has been reported to regulate transcription, cell-cycle progression and the DNA-damage response, independently of its role in chromatin organization. In accordance with its multiple functions, defects in TSPYL2 have been associated with different diseases, mainly cancer and neurodevelopmental abnormalities. In this review we summarize and discuss the multiple cellular functions of TSPYL2, pointing out new and unexpected aspects like a sex-related activity and their relationship with different diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Chromatin is a dynamic cellular structure basically constituted by nucleosomes, which consist of a DNA sequence wrapped around an octameric histones core. Histone synthesis and transport, nucleosome formation and proper chromatin assembly is an ordered and stepwise process guided by histone chaperones. Several families of histone chaperones have been identified and one of them is the nucleosome assembly protein (NAP) superfamily. Members of this family have been involved not only in chromatin constitution and regulation but also in several other cellular processes, such as nucleocytoplasmic shuttling, DNA replication, transcription and cell-cycle regulation. Testis specific protein Y-like 2 (TSPYL2) is a peculiar member of the NAP superfamily of histone chaperone. This protein has been initially isolated as a nuclear antigen in patients affected by discoid lupus erythematosus and as a TGF-β target. Its ability to bind histones has been demonstrated. In addition, TSPYL2 has been reported to regulate transcription, cell-cycle progression and the DNA-damage response, independently of its role in chromatin organization. In accordance with its multiple functions, defects in TSPYL2 have been associated with different diseases, mainly cancer and neurodevelopmental abnormalities. In this review we summarize and discuss the multiple cellular functions of TSPYL2, pointing out new and unexpected aspects like a sex-related activity and their relationship with different diseases. |
Serpieri V; Vezain-Mouchard M; Orsi A; Lecointre M; Mazzotta C; Marguet F; Garbelli A; Marcorelles P; Celli L; Goldenberg A; De Mori R; Drouot N; Petrizzelli F; Janin F; Nicolas G; Smal N; Condoluci C; Marini C; Tran-Mau-Them F; Ruault V; Micalizzi A; Bione S; Mazza T; Pichiecchio A; Ginevrino M; Weckhuysen S; Bedois A; Desnous B; Hermitte L; Rabie G; Kanaan M; Gonzalez BJ; Sabbioneda S; Laquerrière A; Saugier-Veber P; Valente EM Bi-allelic variants in FSD1L cause a neurodevelopmental disorder overlapping with L1 syndrome Journal Article In: American journal of human genetics, vol. 113, iss. 3, pp. 600-615, 2026. @article{%a1.%Y_267,
title = {Bi-allelic variants in FSD1L cause a neurodevelopmental disorder overlapping with L1 syndrome},
author = {Serpieri V and Vezain-Mouchard M and Orsi A and Lecointre M and Mazzotta C and Marguet F and Garbelli A and Marcorelles P and Celli L and Goldenberg A and De Mori R and Drouot N and Petrizzelli F and Janin F and Nicolas G and Smal N and Condoluci C and Marini C and Tran-Mau-Them F and Ruault V and Micalizzi A and Bione S and Mazza T and Pichiecchio A and Ginevrino M and Weckhuysen S and Bedois A and Desnous B and Hermitte L and Rabie G and Kanaan M and Gonzalez BJ and Sabbioneda S and Laquerrière A and Saugier-Veber P and Valente EM},
url = {https://www.sciencedirect.com/science/article/pii/S0002929726000364?via%3Dihub},
doi = {10.1016/j.ajhg.2026.01.014},
year = {2026},
date = {2026-03-16},
journal = {American journal of human genetics},
volume = {113},
issue = {3},
pages = {600-615},
abstract = {Disruption of the complex processes underlying central nervous system development leads to a broad spectrum of brain malformations and neurodevelopmental disorders, often with a genetic cause. Here, we report bi-allelic pathogenic variants in fibronectin type III and SPRY domain-containing 1-like (FSD1L), encoding a protein of unknown function, in eleven individuals, including five fetuses from six unrelated families. The phenotype ranges from severe hydrocephalus, corpus callosum agenesis, and absent pyramid decussation to a neurodevelopmental syndrome characterized by severe intellectual disability, spastic tetraparesis, reduced vision, and epilepsy, associated with corpus callosum agenesis/hypoplasia, mild ventricular dilation, optic nerve hypoplasia, and white matter reduction. This phenotype closely resembles that observed in L1 syndrome, caused by pathogenic variants in L1CAM, encoding a neural adhesion molecule. The knockdown of Fsd1l in mouse embryos recapitulated the ventricular dilation observed in affected fetuses. Immunohistochemical studies in human control fetuses revealed that FSD1L localized to neurons with commissural fate and projection neurons during human development. Induced pluripotent stem cell (iPSC)-derived neural progenitor cells from affected individuals failed to differentiate into premature neurons and to properly form neurospheres while undergoing increased cell death. In neural progenitors, FSD1L localized with microtubules of the mitotic spindle during M phase and to the transition zone and along the axoneme of the primary cilium during interphase. In line with this, fibroblasts from affected individuals exhibited marked alterations of the mitotic spindle and reduced ciliogenesis and ciliary length compared to control cells. Our findings define FSD1L as a microtubule-associated protein implicated in neuronal differentiation, axon guidance, and fasciculation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Disruption of the complex processes underlying central nervous system development leads to a broad spectrum of brain malformations and neurodevelopmental disorders, often with a genetic cause. Here, we report bi-allelic pathogenic variants in fibronectin type III and SPRY domain-containing 1-like (FSD1L), encoding a protein of unknown function, in eleven individuals, including five fetuses from six unrelated families. The phenotype ranges from severe hydrocephalus, corpus callosum agenesis, and absent pyramid decussation to a neurodevelopmental syndrome characterized by severe intellectual disability, spastic tetraparesis, reduced vision, and epilepsy, associated with corpus callosum agenesis/hypoplasia, mild ventricular dilation, optic nerve hypoplasia, and white matter reduction. This phenotype closely resembles that observed in L1 syndrome, caused by pathogenic variants in L1CAM, encoding a neural adhesion molecule. The knockdown of Fsd1l in mouse embryos recapitulated the ventricular dilation observed in affected fetuses. Immunohistochemical studies in human control fetuses revealed that FSD1L localized to neurons with commissural fate and projection neurons during human development. Induced pluripotent stem cell (iPSC)-derived neural progenitor cells from affected individuals failed to differentiate into premature neurons and to properly form neurospheres while undergoing increased cell death. In neural progenitors, FSD1L localized with microtubules of the mitotic spindle during M phase and to the transition zone and along the axoneme of the primary cilium during interphase. In line with this, fibroblasts from affected individuals exhibited marked alterations of the mitotic spindle and reduced ciliogenesis and ciliary length compared to control cells. Our findings define FSD1L as a microtubule-associated protein implicated in neuronal differentiation, axon guidance, and fasciculation. |
Martina MG; Mathez G; Rubini D; Valenti ME; Lachat P; Cristinelli S; Kebbi Beghdadi C; Carlen V; Crespan E; Bianchi E; Opota O; Greub G; Ciuffi A; Gouttenoire J; Radi M; Cagno V Identification of 3-cyanoquinolines as broad-spectrum inhibitors of Monkeypox virus and other sexually transmitted pathogens Journal Article In: Biomedecine & pharmacotherapie, vol. 196, pp. 119080, 2026. @article{%a1.%Y_266,
title = {Identification of 3-cyanoquinolines as broad-spectrum inhibitors of Monkeypox virus and other sexually transmitted pathogens},
author = {Martina MG and Mathez G and Rubini D and Valenti ME and Lachat P and Cristinelli S and Kebbi Beghdadi C and Carlen V and Crespan E and Bianchi E and Opota O and Greub G and Ciuffi A and Gouttenoire J and Radi M and Cagno V},
url = {https://www.sciencedirect.com/science/article/pii/S0753332226001125?via%3Dihub},
doi = {10.1016/j.biopha.2026.119080},
year = {2026},
date = {2026-03-16},
journal = {Biomedecine & pharmacotherapie},
volume = {196},
pages = {119080},
abstract = {Sexually transmitted infections (STIs) remain a major global health concern, contributing significantly to morbidity and facilitating the co-transmission of other pathogens. Recent outbreaks of Monkeypox virus (MPXV) have further underscored the urgent need for broad-spectrum antiviral agents effective against emerging and re-emerging sexually transmissible viruses. We report here the design and synthesis of a series of 3-cyanoquinoline-based Src inhibitors to evaluate their antimicrobial efficacy against sexually transmitted pathogens. Among them, compound 7d demonstrated potent inhibitory activity against MPXV, Herpes simplex virus types 1 and 2, Hepatitis C virus, Human immunodeficiency virus, and Chlamydia trachomatis at non-toxic concentrations. Owing to its broad-spectrum profile and favorable cytotoxicity profile, compound 7d represents a promising candidate for development as a topical microbicide for the prevention and treatment of STIs. Interestingly, the screening also identified compound 7g, which, despite lacking Src inhibitory activity, exhibited selective antiviral activity against members of the Poxviridae family, suggesting the involvement of alternative host-dependent mechanisms that can be further exploited. Both compounds were non-toxic in relevant epithelial and mucosal tissue models. Collectively, these findings highlight the therapeutic potential of 3-cyanoquinoline derivatives as scaffolds for the development of novel broad-spectrum microbicides targeting a range of sexually transmitted pathogens.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sexually transmitted infections (STIs) remain a major global health concern, contributing significantly to morbidity and facilitating the co-transmission of other pathogens. Recent outbreaks of Monkeypox virus (MPXV) have further underscored the urgent need for broad-spectrum antiviral agents effective against emerging and re-emerging sexually transmissible viruses. We report here the design and synthesis of a series of 3-cyanoquinoline-based Src inhibitors to evaluate their antimicrobial efficacy against sexually transmitted pathogens. Among them, compound 7d demonstrated potent inhibitory activity against MPXV, Herpes simplex virus types 1 and 2, Hepatitis C virus, Human immunodeficiency virus, and Chlamydia trachomatis at non-toxic concentrations. Owing to its broad-spectrum profile and favorable cytotoxicity profile, compound 7d represents a promising candidate for development as a topical microbicide for the prevention and treatment of STIs. Interestingly, the screening also identified compound 7g, which, despite lacking Src inhibitory activity, exhibited selective antiviral activity against members of the Poxviridae family, suggesting the involvement of alternative host-dependent mechanisms that can be further exploited. Both compounds were non-toxic in relevant epithelial and mucosal tissue models. Collectively, these findings highlight the therapeutic potential of 3-cyanoquinoline derivatives as scaffolds for the development of novel broad-spectrum microbicides targeting a range of sexually transmitted pathogens. |
Malatesta S; Vigiano Benedetti V; Salviati E; Illi B; Manni I; Middonti E; Rampioni Vinciguerra GL; Licursi V; Troilo F; Colotti G; Cipolla L; Sabbioneda S; Perfetto L; Piaggio G; Bussolino F; Di Nicolantonio F; Campiglia P; Sommella EM; Mori M; Cencioni C; Spallotta F α-ketoglutarate/succinate ratio imbalance impairs thymine DNA glycosylase function and base excision repair process increasing susceptibility to pancreatic cancer Journal Article In: Cell death and disease, vol. 17, iss. 1, pp. 242, 2026. @article{%a1.%Y_265,
title = {α-ketoglutarate/succinate ratio imbalance impairs thymine DNA glycosylase function and base excision repair process increasing susceptibility to pancreatic cancer},
author = {Malatesta S and Vigiano Benedetti V and Salviati E and Illi B and Manni I and Middonti E and Rampioni Vinciguerra GL and Licursi V and Troilo F and Colotti G and Cipolla L and Sabbioneda S and Perfetto L and Piaggio G and Bussolino F and Di Nicolantonio F and Campiglia P and Sommella EM and Mori M and Cencioni C and Spallotta F},
url = {https://www.nature.com/articles/s41419-026-08475-w},
doi = {10.1038/s41419-026-08475-w},
year = {2026},
date = {2026-03-16},
journal = {Cell death and disease},
volume = {17},
issue = {1},
pages = {242},
abstract = {Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with chronic metabolic disorders increasing risk and severity. Prolonged exposure to altered metabolism changes specific metabolite levels, impacting epigenetic landscape contributing neoplastic lesion acquisition. This study examines the interplay between metabolism and epigenetics in dysmetabolic-driven PDAC tumorigenesis, exploiting LSL-KrasG12D;PDX-1-Cre mice (KC mice) exposed to high-fat diet (HFD) and KRAS-mutated human pancreatic ductal epithelial (HPDE) cells. Untargeted metabolomics of HFD-fed KC pancreata reveals altered free fatty acid and elevated S-adenosyl methionine levels during tumorigenesis. Targeted metabolomics shows increased succinate alongside reduced α-ketoglutarate levels. This imbalance suggests an epigenetic derangement, targeting DNA methylation. In KRAS-mutated HPDE cells exposed to altered metabolism, the DNA demethylation complex of ten-to-eleven-translocation methylcytosine 1 and thymine DNA glycosylase (TDG) is disrupted, leading to iterative cytosine modification and apurinic/apyrimidinic (AP) site accumulation. Succinate directly binds TDG at arginine 275, hyperactivating it and increasing AP site formation. This alteration combined with the methylation-prone metabolic environment, impairs the base excision repair pathway by hypermethylating and downmodulating DNA ligases LIG1 and LIG3. This predisposes to genomic instability and pancreatic preneoplastic lesion development. These findings uncover a metabolic-epigenetic axis in dysmetabolic PDAC, highlighting how metabolite-driven epigenetic changes compromise DNA repair and drive tumorigenesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with chronic metabolic disorders increasing risk and severity. Prolonged exposure to altered metabolism changes specific metabolite levels, impacting epigenetic landscape contributing neoplastic lesion acquisition. This study examines the interplay between metabolism and epigenetics in dysmetabolic-driven PDAC tumorigenesis, exploiting LSL-KrasG12D;PDX-1-Cre mice (KC mice) exposed to high-fat diet (HFD) and KRAS-mutated human pancreatic ductal epithelial (HPDE) cells. Untargeted metabolomics of HFD-fed KC pancreata reveals altered free fatty acid and elevated S-adenosyl methionine levels during tumorigenesis. Targeted metabolomics shows increased succinate alongside reduced α-ketoglutarate levels. This imbalance suggests an epigenetic derangement, targeting DNA methylation. In KRAS-mutated HPDE cells exposed to altered metabolism, the DNA demethylation complex of ten-to-eleven-translocation methylcytosine 1 and thymine DNA glycosylase (TDG) is disrupted, leading to iterative cytosine modification and apurinic/apyrimidinic (AP) site accumulation. Succinate directly binds TDG at arginine 275, hyperactivating it and increasing AP site formation. This alteration combined with the methylation-prone metabolic environment, impairs the base excision repair pathway by hypermethylating and downmodulating DNA ligases LIG1 and LIG3. This predisposes to genomic instability and pancreatic preneoplastic lesion development. These findings uncover a metabolic-epigenetic axis in dysmetabolic PDAC, highlighting how metabolite-driven epigenetic changes compromise DNA repair and drive tumorigenesis. |
Terraneo F; Ceccon M; Sapkota O; Zheng T; Brizioli M; Dello Stritto A; Cummings S; Codispoti S; Ossolengo G; Orsenigo F; Magni S; Gottinger A; Mattevi A; Fuxreiter M; Fawzi NL; Lottersberger F; Giavazzi F; d'Adda di Fagagna F The glycine-arginine-rich motif of 53BP1 modulates RNA interactions necessary for its liquid-liquid phase separation during DNA Damage Response Journal Article Forthcoming In: bioRxiv, Forthcoming. @article{%a1.%Y_264,
title = {The glycine-arginine-rich motif of 53BP1 modulates RNA interactions necessary for its liquid-liquid phase separation during DNA Damage Response},
author = {Terraneo F and Ceccon M and Sapkota O and Zheng T and Brizioli M and Dello Stritto A and Cummings S and Codispoti S and Ossolengo G and Orsenigo F and Magni S and Gottinger A and Mattevi A and Fuxreiter M and Fawzi NL and Lottersberger F and Giavazzi F and {d'Adda di Fagagna F}},
url = {https://www.biorxiv.org/content/10.64898/2026.01.30.702603v1},
doi = {10.64898/2026.01.30.702603},
year = {2026},
date = {2026-03-16},
journal = {bioRxiv},
abstract = {The DNA damage response relies on the rapid assembly of repair factors into foci with properties of liquid-liquid phase separation, driven by de novo transcription of damage-induced RNAs. 53BP1 is a key component of these condensates, yet the molecular determinants driving this process remain unknown. Here, through computational, structural and in vitro approaches, we identify the oligomerization domain of 53BP1 and its glycine-arginine-rich (GAR) motif as crucial for RNA interactions and phase separation. Biophysical characterization reveals that 53BP1-RNA condensates can progressively mature into a more stable state, and that GAR mutants display aberrant material properties. Using a cellular model of telomere fusion events, we demonstrate that the GAR motif is essential for 53BP1-mediated DNA repair, which depends on the combined contributions of RNA binding and appropriate condensate biophysical properties. Therefore, RNA-driven 53BP1 condensation is functionally required to maintain genome integrity.},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
The DNA damage response relies on the rapid assembly of repair factors into foci with properties of liquid-liquid phase separation, driven by de novo transcription of damage-induced RNAs. 53BP1 is a key component of these condensates, yet the molecular determinants driving this process remain unknown. Here, through computational, structural and in vitro approaches, we identify the oligomerization domain of 53BP1 and its glycine-arginine-rich (GAR) motif as crucial for RNA interactions and phase separation. Biophysical characterization reveals that 53BP1-RNA condensates can progressively mature into a more stable state, and that GAR mutants display aberrant material properties. Using a cellular model of telomere fusion events, we demonstrate that the GAR motif is essential for 53BP1-mediated DNA repair, which depends on the combined contributions of RNA binding and appropriate condensate biophysical properties. Therefore, RNA-driven 53BP1 condensation is functionally required to maintain genome integrity. |
Soldano S; Weththimuni ML; Oldani A; Girella A; Moyano A; Croce AC; Licchelli M; Gomulski LM; Scolari F Autofluorescence and Fourier transform infrared analyses trace dietary fluorophores and reveal plastic contamination in the gut of mosquito larvae Journal Article Forthcoming In: Scientific reports, Forthcoming. @article{%a1.%Y_263,
title = {Autofluorescence and Fourier transform infrared analyses trace dietary fluorophores and reveal plastic contamination in the gut of mosquito larvae},
author = {Soldano S and Weththimuni ML and Oldani A and Girella A and Moyano A and Croce AC and Licchelli M and Gomulski LM and Scolari F},
url = {https://www.nature.com/articles/s41598-026-38938-1},
doi = {10.1038/s41598-026-38938-1},
year = {2026},
date = {2026-03-16},
journal = {Scientific reports},
abstract = {No abstract available},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
|
Nussey DH; d'Adda di Fagagna F; Bardin AJ; Blau H; Brunet A; Bulavin DV; Guo L; Hara E; Junker JP; Gorbunova V; Mittelbrunn M; Rera M; Reznick J; Seluanov A; Schumacher B; Teeling EC; Valenzano DR; Ye J; Yun MH; Garinis GA; Gilson E Molecular evolution of animal aging Journal Article In: EMBO journal, vol. 45, iss. 7, pp. 2095-2111, 2026. @article{%a1.%Y_262,
title = {Molecular evolution of animal aging},
author = {Nussey DH and {d'Adda di Fagagna F} and Bardin AJ and Blau H and Brunet A and Bulavin DV and Guo L and Hara E and Junker JP and Gorbunova V and Mittelbrunn M and Rera M and Reznick J and Seluanov A and Schumacher B and Teeling EC and Valenzano DR and Ye J and Yun MH and Garinis GA and Gilson E},
url = {https://link.springer.com/article/10.1038/s44318-026-00725-z},
doi = {10.1038/s44318-026-00725-z},
year = {2026},
date = {2026-03-16},
urldate = {2026-03-16},
journal = {EMBO journal},
volume = {45},
issue = {7},
pages = {2095-2111},
abstract = {Comparative biology plays a crucial role in uncovering fundamental biological mechanisms and providing evolutionary models for their variation. This approach is particularly valuable for studying aging, given the remarkable diversity in aging trajectories across the tree of life. Many evolutionary theories of aging were proposed well before the discovery of the molecular mechanisms involved, and they remain largely theoretical. Moreover, the growing number of model organisms and the expanding array of experimental and theoretical approaches used to study aging have often remained compartmentalized. As a result, integrating these diverse insights into a unified framework has become increasingly important. As a step toward this goal, this field perspective outlines general biological mechanisms that help explain the variability in aging patterns and longevity across the animal kingdom.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Comparative biology plays a crucial role in uncovering fundamental biological mechanisms and providing evolutionary models for their variation. This approach is particularly valuable for studying aging, given the remarkable diversity in aging trajectories across the tree of life. Many evolutionary theories of aging were proposed well before the discovery of the molecular mechanisms involved, and they remain largely theoretical. Moreover, the growing number of model organisms and the expanding array of experimental and theoretical approaches used to study aging have often remained compartmentalized. As a result, integrating these diverse insights into a unified framework has become increasingly important. As a step toward this goal, this field perspective outlines general biological mechanisms that help explain the variability in aging patterns and longevity across the animal kingdom. |
Esposito F; Francia S DNA double-strand break response at a glance Journal Article In: Journal of cell science, vol. 139, iss. 4, pp. jcs263423, 2026. @article{%a1.%Y_261,
title = {DNA double-strand break response at a glance},
author = {Esposito F and Francia S},
url = {https://journals.biologists.com/jcs/article-abstract/139/4/jcs263423/370955/DNA-double-strand-break-response-at-a-glance?redirectedFrom=fulltext},
doi = {10.1242/jcs.263423},
year = {2026},
date = {2026-03-16},
urldate = {2026-03-16},
journal = {Journal of cell science},
volume = {139},
issue = {4},
pages = {jcs263423},
abstract = {DNA double-strand breaks (DSBs) are among the most cytotoxic and most frequent lesions that arise in the mammalian genome; they occur as a result of both external insults and internal metabolic activities. Failures in damage signalling and repair of DSBs can result in permanent cell cycle arrest, cellular senescence, cell death or the accumulation of mutations and genomic instability - events that ultimately disrupt tissue homeostasis. To reduce these detrimental outcomes, cells have evolved a sophisticated and tightly coordinated network of mechanisms for detecting, signalling and repairing DNA lesions, collectively known as the DNA damage response (DDR). Repair occurs within the chromatin landscape, with DDR sensors, mediators, signalling kinases and ubiquitin ligases rapidly recruited to the site of damage. Simultaneously, local chromatin modifications and remodelling take place, which also modulate local transcriptional activity. More complex chromatin dynamics are subsequently orchestrated within the three-dimensional nuclear space - persistent DSBs are actively relocated to specialized nuclear domains and chromatin compartments undergo spatial reorganization to facilitate efficient repair. In this Cell Science at a Glance article and the accompanying poster, we explore the interplay between local and global chromatin dynamics that coordinate DSB repair and preserve genome integrity within the context of a highly dynamic epigenome.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DNA double-strand breaks (DSBs) are among the most cytotoxic and most frequent lesions that arise in the mammalian genome; they occur as a result of both external insults and internal metabolic activities. Failures in damage signalling and repair of DSBs can result in permanent cell cycle arrest, cellular senescence, cell death or the accumulation of mutations and genomic instability - events that ultimately disrupt tissue homeostasis. To reduce these detrimental outcomes, cells have evolved a sophisticated and tightly coordinated network of mechanisms for detecting, signalling and repairing DNA lesions, collectively known as the DNA damage response (DDR). Repair occurs within the chromatin landscape, with DDR sensors, mediators, signalling kinases and ubiquitin ligases rapidly recruited to the site of damage. Simultaneously, local chromatin modifications and remodelling take place, which also modulate local transcriptional activity. More complex chromatin dynamics are subsequently orchestrated within the three-dimensional nuclear space - persistent DSBs are actively relocated to specialized nuclear domains and chromatin compartments undergo spatial reorganization to facilitate efficient repair. In this Cell Science at a Glance article and the accompanying poster, we explore the interplay between local and global chromatin dynamics that coordinate DSB repair and preserve genome integrity within the context of a highly dynamic epigenome. |
Di Pasqua LG; Lotti S; Trucchi M; Palladini G; Croce AC; Protopapa F; Feletti F; Kauschke SG; Sun P; Vairetti M; Ferrigno A Complex I Modulator BI4500 Reduces MASH by Limiting Oxidative Stress and Reprogramming Lipid Metabolism via AMPK in MCD Rats Journal Article In: Antioxidants, vol. 15, iss. 1, 2026. @article{%a1.%Y_260,
title = {Complex I Modulator BI4500 Reduces MASH by Limiting Oxidative Stress and Reprogramming Lipid Metabolism via AMPK in MCD Rats},
author = {Di Pasqua LG and Lotti S and Trucchi M and Palladini G and Croce AC and Protopapa F and Feletti F and Kauschke SG and Sun P and Vairetti M and Ferrigno A},
url = {https://www.mdpi.com/2076-3921/15/1/82},
doi = {10.3390/antiox15010082},
year = {2026},
date = {2026-02-04},
journal = {Antioxidants},
volume = {15},
issue = {1},
abstract = {Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a multifactorial liver disease in which mitochondrial dysfunction, oxidative stress, and inflammation play key roles in driving the progression toward metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Dysfunctional mitochondria generate excess reactive oxygen species (ROS), impair antioxidant defenses, activate pro-inflammatory pathways and hepatic stellate cells, and perpetuate liver injury. Mitochondrial Complex I is a major ROS source, particularly under conditions of dysregulated energy metabolism. Since Complex I inhibition by metformin was shown to reduce ROS and activate the adenosine monophosphate-activated protein kinase (AMPK), this study aimed to evaluate whether a novel Complex I Modulator (CIM, BI4500) could attenuate oxidative stress, inflammation, and consequently reduce lipid accumulation and fibrosis in a methionine- and choline-deficient diet (MCD)-fed rat model of MASH. Methods: Rats were fed an MCD or an isocaloric control diet for six weeks. From week four, animals received daily oral treatment with CIM (10 mg/kg) or vehicle (Natrosol). At the endpoint, liver tissue was collected for histological, biochemical, and molecular analyses. Lipid droplet area, inflammatory infiltration, and collagen deposition were evaluated on tissue sections; total lipid content and oxidative stress markers were assessed in homogenates and isolated mitochondria. Molecular pathways related to oxidative stress, lipid metabolism, and fibrosis were assessed at protein and mRNA levels. Results: CIM treatment significantly reduced oxidative stress (ROS, lipid peroxidation, nitrogen species), promoting AMPK activation and metabolic reprogramming. This included increased expression of peroxisome proliferator-activated receptor alpha (PPAR-α) and its target genes, and decreased sterol regulatory element binding protein-1c (SREBP-1c)-driven lipogenesis. These changes halted fibrosis progression, as confirmed by Picro-Sirius Red staining and fibrosis markers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a multifactorial liver disease in which mitochondrial dysfunction, oxidative stress, and inflammation play key roles in driving the progression toward metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Dysfunctional mitochondria generate excess reactive oxygen species (ROS), impair antioxidant defenses, activate pro-inflammatory pathways and hepatic stellate cells, and perpetuate liver injury. Mitochondrial Complex I is a major ROS source, particularly under conditions of dysregulated energy metabolism. Since Complex I inhibition by metformin was shown to reduce ROS and activate the adenosine monophosphate-activated protein kinase (AMPK), this study aimed to evaluate whether a novel Complex I Modulator (CIM, BI4500) could attenuate oxidative stress, inflammation, and consequently reduce lipid accumulation and fibrosis in a methionine- and choline-deficient diet (MCD)-fed rat model of MASH. Methods: Rats were fed an MCD or an isocaloric control diet for six weeks. From week four, animals received daily oral treatment with CIM (10 mg/kg) or vehicle (Natrosol). At the endpoint, liver tissue was collected for histological, biochemical, and molecular analyses. Lipid droplet area, inflammatory infiltration, and collagen deposition were evaluated on tissue sections; total lipid content and oxidative stress markers were assessed in homogenates and isolated mitochondria. Molecular pathways related to oxidative stress, lipid metabolism, and fibrosis were assessed at protein and mRNA levels. Results: CIM treatment significantly reduced oxidative stress (ROS, lipid peroxidation, nitrogen species), promoting AMPK activation and metabolic reprogramming. This included increased expression of peroxisome proliferator-activated receptor alpha (PPAR-α) and its target genes, and decreased sterol regulatory element binding protein-1c (SREBP-1c)-driven lipogenesis. These changes halted fibrosis progression, as confirmed by Picro-Sirius Red staining and fibrosis markers. |
Lodola C; Pallotta MM; Manetti F; Governa P; Crespan E; Maga G; Secchi M Dissecting the Interaction Domains of SARS-CoV-2 Nucleocapsid Protein and Human RNA Helicase DDX3X and Search for Potential Inhibitors Journal Article In: International journal of molecular sciences, vol. 27, iss. 2, pp. 672, 2026. @article{%a1.%Y_259,
title = {Dissecting the Interaction Domains of SARS-CoV-2 Nucleocapsid Protein and Human RNA Helicase DDX3X and Search for Potential Inhibitors},
author = {Lodola C and Pallotta MM and Manetti F and Governa P and Crespan E and Maga G and Secchi M},
url = {https://www.mdpi.com/1422-0067/27/2/672},
doi = {10.3390/ijms27020672},
year = {2026},
date = {2026-02-04},
urldate = {2026-02-04},
journal = {International journal of molecular sciences},
volume = {27},
issue = {2},
pages = {672},
abstract = {The SARS-CoV-2 nucleocapsid protein (Np) plays multifunctional roles in the viral life cycle. By interacting with host cellular proteins, Np regulates viral RNA transcription, replication, and immune evasion. It controls genome packaging and counteracts host RNA interference mediated antiviral responses through its RNA binding activity. Previous studies revealed a physical interaction between Np and DDX3X, a human DEAD-box RNA helicase that facilitates the replication of several viruses. This interaction enhances Np affinity for double-stranded RNA and inhibits DDX3X helicase activity. Since Np-RNA binding activity promotes ribonucleoprotein complex formation, targeting this interaction is a promising antiviral strategy. We generated truncated protein variants to define interaction regions between Np and DDX3X. Using AlphaFold modelling, we identified RecA2 as the key DDX3X domain involved in Np binding. Finally, to disrupt Np-RNA complex formation, we screened a small molecule library of putative binders of Np N-terminal region and identified two candidate inhibitors for further development.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The SARS-CoV-2 nucleocapsid protein (Np) plays multifunctional roles in the viral life cycle. By interacting with host cellular proteins, Np regulates viral RNA transcription, replication, and immune evasion. It controls genome packaging and counteracts host RNA interference mediated antiviral responses through its RNA binding activity. Previous studies revealed a physical interaction between Np and DDX3X, a human DEAD-box RNA helicase that facilitates the replication of several viruses. This interaction enhances Np affinity for double-stranded RNA and inhibits DDX3X helicase activity. Since Np-RNA binding activity promotes ribonucleoprotein complex formation, targeting this interaction is a promising antiviral strategy. We generated truncated protein variants to define interaction regions between Np and DDX3X. Using AlphaFold modelling, we identified RecA2 as the key DDX3X domain involved in Np binding. Finally, to disrupt Np-RNA complex formation, we screened a small molecule library of putative binders of Np N-terminal region and identified two candidate inhibitors for further development. |
Zannini L; Aliprandi S; Delia D; Buscemi G Daxx-Dependent H3.3 Deposition Promotes Double-Strand Breaks Repair by Homologous Recombination Journal Article In: Cells, vol. 15, iss. 2, no 162, 2026. @article{%a1.%Y_258,
title = {Daxx-Dependent H3.3 Deposition Promotes Double-Strand Breaks Repair by Homologous Recombination},
author = {Zannini L and Aliprandi S and Delia D and Buscemi G},
url = {https://www.mdpi.com/2073-4409/15/2/162},
doi = {10.3390/cells15020162},
year = {2026},
date = {2026-02-04},
journal = {Cells},
volume = {15},
number = {162},
issue = {2},
abstract = {DNA double-strand breaks (DSBs) can be induced by cellular byproducts or genotoxic agents. Improper processing of these lesions leads to increased genome instability, which constitutes a hallmark of pathological conditions and fuels carcinogenesis. DSBs are primarily repaired by homologous recombination (HR) and non-homologous end joining (NHEJ) and the proper balance between these two pathways is finely modulated by specific molecular events. Here, we report that the histone chaperone DAXX plays a fundamental role in the response to DSBs. Indeed, in human cells, DSBs induce ATM/ATR-dependent phosphorylation of DAXX on serine 424 and 712 and promote its binding to chromatin and the deposition of the histone variant H3.3 in proximity to DNA breaks. Enrichment of H3.3 at DSBs promotes 53BP1 recruitment to these lesions and the repair of DNA breaks by HR pathways. Moreover, H3.3-specific post translational modifications, particularly K36 tri-methylation, play a key role in these processes. Altogether, these findings indicate that DAXX and H3.3 mutations may contribute to tumorigenesis-enhancing genome instability.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DNA double-strand breaks (DSBs) can be induced by cellular byproducts or genotoxic agents. Improper processing of these lesions leads to increased genome instability, which constitutes a hallmark of pathological conditions and fuels carcinogenesis. DSBs are primarily repaired by homologous recombination (HR) and non-homologous end joining (NHEJ) and the proper balance between these two pathways is finely modulated by specific molecular events. Here, we report that the histone chaperone DAXX plays a fundamental role in the response to DSBs. Indeed, in human cells, DSBs induce ATM/ATR-dependent phosphorylation of DAXX on serine 424 and 712 and promote its binding to chromatin and the deposition of the histone variant H3.3 in proximity to DNA breaks. Enrichment of H3.3 at DSBs promotes 53BP1 recruitment to these lesions and the repair of DNA breaks by HR pathways. Moreover, H3.3-specific post translational modifications, particularly K36 tri-methylation, play a key role in these processes. Altogether, these findings indicate that DAXX and H3.3 mutations may contribute to tumorigenesis-enhancing genome instability. |
Storaci AM; de Filippo MR; Franzi S; Mansour N; Lopez G; Molisso MT; Zadra G; Brevi M; Gianazza E; Banfi C; Bianchi C; Garulli G; Mendogni P; Nosotti M; Blasi F; Morlacchi LC; Palleschi A; Vaira V Analysis of BAL extracellular vesicles unveils NF-κB activation at the onset of chronic lung allograft dysfunction Journal Article In: Clinical science, vol. 140, iss. 1, pp. 97-114, 2026. @article{%a1.%Y_257,
title = {Analysis of BAL extracellular vesicles unveils NF-κB activation at the onset of chronic lung allograft dysfunction},
author = {Storaci AM and de Filippo MR and Franzi S and Mansour N and Lopez G and Molisso MT and Zadra G and Brevi M and Gianazza E and Banfi C and Bianchi C and Garulli G and Mendogni P and Nosotti M and Blasi F and Morlacchi LC and Palleschi A and Vaira V},
url = {https://portlandpress.com/clinsci/article-abstract/140/1/97/237053/Analysis-of-BAL-extracellular-vesicles-unveils-NF?redirectedFrom=fulltext},
doi = {10.1042/CS20258651},
year = {2026},
date = {2026-02-04},
journal = {Clinical science},
volume = {140},
issue = {1},
pages = {97-114},
abstract = {The onset of chronic lung allograft dysfunction (CLAD) represents the greatest long-term challenge in lung transplantation (LT). Here we aimed to identify early molecular signals of CLAD by analyzing the effects of bronchoalveolar lavage (BAL)-derived extracellular vesicles (EVs) on airway cells and validating these findings in patient lung tissues. In our BAL biobank, we identified 13 LT patients with a BAL sample at CLAD diagnosis and 13 patients with a stable graft function and a BAL sample obtained at least 12 months post LT (Ctrl). All patients were then followed for at least 18 months. EVs were isolated, immunophenotyped, and co-cultured with airway cells. The cells' transcriptome and proteome were profiled. Selected targets were validated by immunohistochemistry. Logistic regression and survival analyses were performed for prediction of CLAD progression. During follow-up, 7 CLAD patients experienced allograft dysfunction aggravation, and one control developed CLAD. CLAD patients showed more EVs originating from epithelial cells and leukocytes than stable LT recipients. Exposure of airway cells to CLAD-EVs led to the up-regulation of p70S6K and canonical NF-κB signaling, altering their intracellular and extracellular proteome. Activation of NF-κB was also detected at the onset of CLAD in transbronchial biopsies and BAL cytology, and it persisted throughout the progression to end-stage CLAD. RelA overexpression was associated with poorer graft performance and worse outcomes. RelA-driven NF-κB activation is a key factor in the development of CLAD by promoting persistent inflammation. This pathway may be a promising therapeutic target to improve long-term graft survival after LT.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The onset of chronic lung allograft dysfunction (CLAD) represents the greatest long-term challenge in lung transplantation (LT). Here we aimed to identify early molecular signals of CLAD by analyzing the effects of bronchoalveolar lavage (BAL)-derived extracellular vesicles (EVs) on airway cells and validating these findings in patient lung tissues. In our BAL biobank, we identified 13 LT patients with a BAL sample at CLAD diagnosis and 13 patients with a stable graft function and a BAL sample obtained at least 12 months post LT (Ctrl). All patients were then followed for at least 18 months. EVs were isolated, immunophenotyped, and co-cultured with airway cells. The cells' transcriptome and proteome were profiled. Selected targets were validated by immunohistochemistry. Logistic regression and survival analyses were performed for prediction of CLAD progression. During follow-up, 7 CLAD patients experienced allograft dysfunction aggravation, and one control developed CLAD. CLAD patients showed more EVs originating from epithelial cells and leukocytes than stable LT recipients. Exposure of airway cells to CLAD-EVs led to the up-regulation of p70S6K and canonical NF-κB signaling, altering their intracellular and extracellular proteome. Activation of NF-κB was also detected at the onset of CLAD in transbronchial biopsies and BAL cytology, and it persisted throughout the progression to end-stage CLAD. RelA overexpression was associated with poorer graft performance and worse outcomes. RelA-driven NF-κB activation is a key factor in the development of CLAD by promoting persistent inflammation. This pathway may be a promising therapeutic target to improve long-term graft survival after LT. |
Sabbioni S; Guerriero P; Shankaraiah RC; Masatti L; Michilli A; Bassi C; D'Abundo L; Moshiri F; De Siena B; Simoni E; Astolfi L; Gramantieri L; Roncarati R; Elamin BK; Bonora M; Pinton P; Croce CM; Negrini M; Callegari E Targeting metabolic vulnerabilities: REV-ERB agonist SR9009 potentiates sorafenib efficacy in liver cancer Journal Article Forthcoming In: Cell death & differentiation, Forthcoming. @article{%a1.%Y_256,
title = {Targeting metabolic vulnerabilities: REV-ERB agonist SR9009 potentiates sorafenib efficacy in liver cancer},
author = {Sabbioni S and Guerriero P and Shankaraiah RC and Masatti L and Michilli A and Bassi C and D'Abundo L and Moshiri F and De Siena B and Simoni E and Astolfi L and Gramantieri L and Roncarati R and Elamin BK and Bonora M and Pinton P and Croce CM and Negrini M and Callegari E},
url = {https://www.nature.com/articles/s41420-026-02940-3},
doi = {10.1038/s41420-026-02940-3},
year = {2026},
date = {2026-02-04},
journal = {Cell death & differentiation},
abstract = {Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of cancer-related death worldwide. The prognosis is poor, with a median survival of 12-15 months in patients with advanced-stage disease. Early diagnosis and the development of new, more effective therapeutic strategies are needed to address the challenges posed by this malignancy. Although immune checkpoint inhibitors have replaced multikinase inhibitors as first-line therapy, sorafenib continues to represent a valuable option for patients with contraindications to newer treatments. Based on genome-wide RNA-seq analysis, which identified mitochondrial oxidative phosphorylation (OxPhos) and Hmox1 upregulation as potential pro-survival mechanisms in sorafenib-resistant cells, we investigated whether SR9009, a synthetic agonist of the nuclear receptor REV-ERBα/β, heme competitor, and inhibitor of mitochondrial respiration, could enhance the antitumor efficacy of sorafenib in liver cancer models. Co-treatment with SR9009 and sorafenib significantly enhanced cytotoxic effects in both mouse and human liver cancer cells. This synergistic activity was associated with increased levels of free heme and a complete inhibition of mitochondrial OxPhos. In vivo xenograft studies confirmed that the combination was effective even in sorafenib-resistant tumors. Furthermore, in a N-Nitrosodiethylamine (DEN)-induced HCC model, the combination therapy led to a reduction in size in over 90% of tumor nodules, representing a significant improvement over sorafenib alone. The combination was well tolerated, with no evident signs of acute toxicity. These findings support the concept that the efficacy of anticancer therapies can be enhanced by targeting the metabolic adaptations that tumor cells rely on for survival. Combining sorafenib with agents like SR9009, that disrupt metabolic homeostasis, may offer a promising strategy for treating advanced HCC.},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of cancer-related death worldwide. The prognosis is poor, with a median survival of 12-15 months in patients with advanced-stage disease. Early diagnosis and the development of new, more effective therapeutic strategies are needed to address the challenges posed by this malignancy. Although immune checkpoint inhibitors have replaced multikinase inhibitors as first-line therapy, sorafenib continues to represent a valuable option for patients with contraindications to newer treatments. Based on genome-wide RNA-seq analysis, which identified mitochondrial oxidative phosphorylation (OxPhos) and Hmox1 upregulation as potential pro-survival mechanisms in sorafenib-resistant cells, we investigated whether SR9009, a synthetic agonist of the nuclear receptor REV-ERBα/β, heme competitor, and inhibitor of mitochondrial respiration, could enhance the antitumor efficacy of sorafenib in liver cancer models. Co-treatment with SR9009 and sorafenib significantly enhanced cytotoxic effects in both mouse and human liver cancer cells. This synergistic activity was associated with increased levels of free heme and a complete inhibition of mitochondrial OxPhos. In vivo xenograft studies confirmed that the combination was effective even in sorafenib-resistant tumors. Furthermore, in a N-Nitrosodiethylamine (DEN)-induced HCC model, the combination therapy led to a reduction in size in over 90% of tumor nodules, representing a significant improvement over sorafenib alone. The combination was well tolerated, with no evident signs of acute toxicity. These findings support the concept that the efficacy of anticancer therapies can be enhanced by targeting the metabolic adaptations that tumor cells rely on for survival. Combining sorafenib with agents like SR9009, that disrupt metabolic homeostasis, may offer a promising strategy for treating advanced HCC. |
Choudhary R; Munoz JC; Beckerman I; Rebottaro ML; Bastianello G; Bouvier LA; Foiani M; Munoz MJ RNA polymerase II degradation triggered by DNA repair occurs in trans and independently of how the lesion is recognized Journal Article In: Nucleic acids research, vol. 54, iss. 1, 2026. @article{%a1.%Y_255,
title = {RNA polymerase II degradation triggered by DNA repair occurs in trans and independently of how the lesion is recognized},
author = {Choudhary R and Munoz JC and Beckerman I and Rebottaro ML and Bastianello G and Bouvier LA and Foiani M and Munoz MJ},
url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC12781871/},
doi = {10.1093/nar/gkaf1416},
year = {2026},
date = {2026-02-04},
journal = {Nucleic acids research},
volume = {54},
issue = {1},
abstract = {In response to DNA damage, RPB1, the catalytic subunit of RNA Polymerase II (RNAPII), is degraded by the ubiquitin-proteasome system. Degradation models only consider transcriptionally engaged molecules, where a stalled RNAPII complex functions as a lesion-recognition factor, and its RPB1 subunit is proposed to be subsequently degraded to facilitate access of lesion-processing nucleotide excision repair (NER) factors. This transcription-coupled repair is complemented by the global genome repair (GG-NER) system, where lesions are recognized by the XPC and DDB2 factors. Here, we show that RPB1 degradation is controlled in trans by a pathway that depends on lesion processing by NER, irrespectively of whether the lesion is recognized by RNAPII itself or by XPC-DDB2. Incomplete repair due to absence of lesion-processing factors (XPA, XPB, XPD, XPF, or XPG) enhances RPB1 degradation, indicating that the signal controlling RPB1 abundance is started by lesion recognition and continues until DNA repair is completed. Consistent with an in trans mechanism, damage-induced RPB1 degradation is not restricted to active nor phosphorylated RPB1 molecules and depends on Cullin-RING ubiquitin ligases. These findings uncover a repair-dependent mechanism controlling RPB1 levels and provide a rationale for the control of gene expression under stress, where more damage implies more repair and less RPB1 levels, hence restricting RNAPII activity.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In response to DNA damage, RPB1, the catalytic subunit of RNA Polymerase II (RNAPII), is degraded by the ubiquitin-proteasome system. Degradation models only consider transcriptionally engaged molecules, where a stalled RNAPII complex functions as a lesion-recognition factor, and its RPB1 subunit is proposed to be subsequently degraded to facilitate access of lesion-processing nucleotide excision repair (NER) factors. This transcription-coupled repair is complemented by the global genome repair (GG-NER) system, where lesions are recognized by the XPC and DDB2 factors. Here, we show that RPB1 degradation is controlled in trans by a pathway that depends on lesion processing by NER, irrespectively of whether the lesion is recognized by RNAPII itself or by XPC-DDB2. Incomplete repair due to absence of lesion-processing factors (XPA, XPB, XPD, XPF, or XPG) enhances RPB1 degradation, indicating that the signal controlling RPB1 abundance is started by lesion recognition and continues until DNA repair is completed. Consistent with an in trans mechanism, damage-induced RPB1 degradation is not restricted to active nor phosphorylated RPB1 molecules and depends on Cullin-RING ubiquitin ligases. These findings uncover a repair-dependent mechanism controlling RPB1 levels and provide a rationale for the control of gene expression under stress, where more damage implies more repair and less RPB1 levels, hence restricting RNAPII activity. |
Cavazzoni A; Pagano Mariano M; Palladini A; Digiacomo G; La Monica S; Bonelli M; Galetti M; Pace I; Roncarati R; Giovannetti E; Aretini P; Minari R; Treccani M; Pluchino M; Lagrasta CA; Angelicola S; Mazzaschi G; Bordi P; Gelsomino F; Agustoni F; Petronini PG; Tiseo M; Ferracin M; Alfieri R Targeting HGF/MET and CXCL1/CXCR2 axes bypasses resistance to KRASG12C inhibitors in NSCLC Journal Article In: Lung Cancer, vol. 213, pp. 108939, 2026. @article{%a1.%Y_254,
title = {Targeting HGF/MET and CXCL1/CXCR2 axes bypasses resistance to KRASG12C inhibitors in NSCLC},
author = {Cavazzoni A and Pagano Mariano M and Palladini A and Digiacomo G and La Monica S and Bonelli M and Galetti M and Pace I and Roncarati R and Giovannetti E and Aretini P and Minari R and Treccani M and Pluchino M and Lagrasta CA and Angelicola S and Mazzaschi G and Bordi P and Gelsomino F and Agustoni F and Petronini PG and Tiseo M and Ferracin M and Alfieri R},
url = {https://www.sciencedirect.com/science/article/pii/S0169500226000346?via%3Dihub},
doi = {10.1016/j.lungcan.2026.108939},
year = {2026},
date = {2026-02-04},
urldate = {2026-02-04},
journal = {Lung Cancer},
volume = {213},
pages = {108939},
abstract = {Background: Resistance to KRASG12C inhibitors sotorasib and adagrasib, approved for KRASG12C-mutant advanced Non-Small Cell Lung Cancer (NSCLC), involves multiple subclonal events, raising significant concerns about overcoming the resistant phenotype. Cytokines, chemokines, and growth factors are key mediators of drug resistance and targeting their signaling pathways is an emerging strategy in cancer therapy. Methods: We generated cell clones from KRASG12C-mutated NSCLC cells treated with KRAS inhibitors and cell cultures from a sotorasib-resistant patient-derived xenograft (PDX). Gene mutations and changes in gene expression were evaluated using NGS, RNAseq. The mRNA and protein levels encoded by the Hepatocyte Growth Factor (HGF) and CXCL1 genes were quantified using RT-PCR and ELISA assay. The effect of drug combination was obtained by the Sulforhodamine-B assay and analyzed by Combenefit Software. Cell death was detected by Annexin-V assay. Cell signaling and epithelial-to-mesenchymal transition were evaluated by Western blotting. Results: NSCLC cell clones and PDX cell cultures with acquired and intrinsic resistance to KRASG12C inhibitors exhibited elevated levels of CXCL1 and HGF expression and secretion, with activation of CXCR2 and c-MET signalling pathways. The combination of CXCR2 and c-MET inhibitors led to synergistic inhibition of cell growth and reduced cell viability by inhibiting the ERK1/2 and AKT signalling pathways. This combination also reversed EMT and induced apoptosis in sotorasib- and adagrasib-resistant clones, regardless of the genetic alterations responsible for resistance. Conclusions: CXCL1/CXCR2 and HGF/c-MET may represent compensatory pathways that sustain proliferation and survival in resistance to KRASG12C inhibitors. The simultaneous blockade of these signals may offer a novel strategy for bypassing resistance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: Resistance to KRASG12C inhibitors sotorasib and adagrasib, approved for KRASG12C-mutant advanced Non-Small Cell Lung Cancer (NSCLC), involves multiple subclonal events, raising significant concerns about overcoming the resistant phenotype. Cytokines, chemokines, and growth factors are key mediators of drug resistance and targeting their signaling pathways is an emerging strategy in cancer therapy. Methods: We generated cell clones from KRASG12C-mutated NSCLC cells treated with KRAS inhibitors and cell cultures from a sotorasib-resistant patient-derived xenograft (PDX). Gene mutations and changes in gene expression were evaluated using NGS, RNAseq. The mRNA and protein levels encoded by the Hepatocyte Growth Factor (HGF) and CXCL1 genes were quantified using RT-PCR and ELISA assay. The effect of drug combination was obtained by the Sulforhodamine-B assay and analyzed by Combenefit Software. Cell death was detected by Annexin-V assay. Cell signaling and epithelial-to-mesenchymal transition were evaluated by Western blotting. Results: NSCLC cell clones and PDX cell cultures with acquired and intrinsic resistance to KRASG12C inhibitors exhibited elevated levels of CXCL1 and HGF expression and secretion, with activation of CXCR2 and c-MET signalling pathways. The combination of CXCR2 and c-MET inhibitors led to synergistic inhibition of cell growth and reduced cell viability by inhibiting the ERK1/2 and AKT signalling pathways. This combination also reversed EMT and induced apoptosis in sotorasib- and adagrasib-resistant clones, regardless of the genetic alterations responsible for resistance. Conclusions: CXCL1/CXCR2 and HGF/c-MET may represent compensatory pathways that sustain proliferation and survival in resistance to KRASG12C inhibitors. The simultaneous blockade of these signals may offer a novel strategy for bypassing resistance. |
Botta E; Fawcett H; Orioli D; Fassihi H; Lehmann AR Unusual Disease-Progression in Two Siblings With Xeroderma Pigmentosum Group G Journal Article In: Clinical genetics, vol. 109, iss. 5, pp. 984-985, 2026. @article{%a1.%Y_253,
title = {Unusual Disease-Progression in Two Siblings With Xeroderma Pigmentosum Group G},
author = {Botta E and Fawcett H and Orioli D and Fassihi H and Lehmann AR},
url = {https://onlinelibrary.wiley.com/doi/10.1111/cge.70129},
doi = {10.1111/cge.70129},
year = {2026},
date = {2026-02-04},
urldate = {2026-02-04},
journal = {Clinical genetics},
volume = {109},
issue = {5},
pages = {984-985},
abstract = {Protein truncation mutations in the gene for XPG nuclease cause a very severe clinical phenotype. Two siblings have splicing mutations, which result in in-frame deletions and a less severe phenotype.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Protein truncation mutations in the gene for XPG nuclease cause a very severe clinical phenotype. Two siblings have splicing mutations, which result in in-frame deletions and a less severe phenotype. |
Veniali G; Lanzafame M DBR1 and the RNAopathy Landscape of Trichothiodystrophy Journal Article In: Journal of investigative dermatology, vol. 146, iss. 2, pp. 298-301, 2026. @article{%a1.%Y_238,
title = {DBR1 and the RNAopathy Landscape of Trichothiodystrophy},
author = {Veniali G and Lanzafame M},
url = {https://www.sciencedirect.com/science/article/abs/pii/S0022202X25023139?via%3Dihub},
doi = {10.1016/j.jid.2025.07.011},
year = {2026},
date = {2026-01-05},
urldate = {2025-10-10},
journal = {Journal of investigative dermatology},
volume = {146},
issue = {2},
pages = {298-301},
abstract = {not available - Commentary to "RNA Lariat-Debranching Enzyme (DBR1) Variations in Sabinas Brittle Hair Syndrome Form of Trichothiodystrophy: A Trichothiodystrophy-Causing Gene" Sikandar G. Khan, Wenelia Baghoomian, Christiane Kuschal-Tauzon, Deborah Tamura, Maxwell P. Lee, John J. DiGiovanna, Rodrigo Cepeda-Valdes, Julio Salas-Alanis, Kenneth H. Kraemer (DOI: https://doi.org/10.1016/j.jid.2025.06.1591)},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
not available - Commentary to "RNA Lariat-Debranching Enzyme (DBR1) Variations in Sabinas Brittle Hair Syndrome Form of Trichothiodystrophy: A Trichothiodystrophy-Causing Gene" Sikandar G. Khan, Wenelia Baghoomian, Christiane Kuschal-Tauzon, Deborah Tamura, Maxwell P. Lee, John J. DiGiovanna, Rodrigo Cepeda-Valdes, Julio Salas-Alanis, Kenneth H. Kraemer (DOI: https://doi.org/10.1016/j.jid.2025.06.1591) |
Di Pasqua LG; Palladini G; Croce AC; Milanesi G; Cavallo M; Adorini L; Ferrigno A; Vairetti M Farnesoid X Receptor Agonist INT-787 Inhibits Hepatic Mitochondrial Dysfunction in a Diet-Induced ob/ob Mouse Model of MASH Journal Article In: International journal of molecular sciences, vol. 26, iss. 2, pp. 11023, 2025. @article{%a1.%Y_247,
title = {Farnesoid X Receptor Agonist INT-787 Inhibits Hepatic Mitochondrial Dysfunction in a Diet-Induced ob/ob Mouse Model of MASH},
author = {Di Pasqua LG and Palladini G and Croce AC and Milanesi G and Cavallo M and Adorini L and Ferrigno A and Vairetti M},
url = {https://www.mdpi.com/1422-0067/26/22/11023},
doi = {10.3390/ijms262211023},
year = {2025},
date = {2025-12-22},
urldate = {2025-12-22},
journal = {International journal of molecular sciences},
volume = {26},
issue = {2},
pages = {11023},
abstract = {This study evaluated the protective role of farnesoid-X-receptor (FXR) agonist INT-787 in the control of mitochondrial changes using a metabolic dysfunction-associated steatohepatitis (MASH) model. Lep-ob/ob mice were fed a control diet (CD) for 21 weeks (wks), or a high-fat diet (HFD) for 9 or 21 wks; in the 21 wk HFD groups, INT-787 (30 mg/kg/day) dosed via HFD admixture was added. The hepatic ATP, ROS, GSH and MIC19, which stabilizes the structure of inner mitochondrial membrane (IMM), were quantified. Transmission electron microscopy (TEM) analysis was also performed. INT-787 increased hepatic ATP, which was downregulated after HFD 9 and 21 wks. Hepatic ROS increased and GSH decreased after 21 wks and were recovered by INT-787. MIC19 mRNA level decreased after HFD 21 wks, and it was completely restored after INT-787 administration. TEM analysis showed that INT-787 reverted the mitochondrial alterations as documented by restored mitochondrial length, number of mitochondrial cristae junctions (CJs), and distance between endoplasmic reticulum (ER) and outer mitochondrial membrane (OMM) when compared with HFD groups. These results underline the involvement of the FXR pathway in the control of mitochondrial damage, thus revealing a previously undiscovered mechanism mediated by FXR activation: the upregulation of IMM protein MIC19, which is essential for maintaining cristae integrity and mitochondrial function.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
This study evaluated the protective role of farnesoid-X-receptor (FXR) agonist INT-787 in the control of mitochondrial changes using a metabolic dysfunction-associated steatohepatitis (MASH) model. Lep-ob/ob mice were fed a control diet (CD) for 21 weeks (wks), or a high-fat diet (HFD) for 9 or 21 wks; in the 21 wk HFD groups, INT-787 (30 mg/kg/day) dosed via HFD admixture was added. The hepatic ATP, ROS, GSH and MIC19, which stabilizes the structure of inner mitochondrial membrane (IMM), were quantified. Transmission electron microscopy (TEM) analysis was also performed. INT-787 increased hepatic ATP, which was downregulated after HFD 9 and 21 wks. Hepatic ROS increased and GSH decreased after 21 wks and were recovered by INT-787. MIC19 mRNA level decreased after HFD 21 wks, and it was completely restored after INT-787 administration. TEM analysis showed that INT-787 reverted the mitochondrial alterations as documented by restored mitochondrial length, number of mitochondrial cristae junctions (CJs), and distance between endoplasmic reticulum (ER) and outer mitochondrial membrane (OMM) when compared with HFD groups. These results underline the involvement of the FXR pathway in the control of mitochondrial damage, thus revealing a previously undiscovered mechanism mediated by FXR activation: the upregulation of IMM protein MIC19, which is essential for maintaining cristae integrity and mitochondrial function. |
Balaha M; De Filippis B; Rapino M; Kazimierczak P; Przekora A; Esmail T; Toto EC; Petrucci G; Canal C; Cataldi A; di Giacomo V CAPE Derivatives as Potent Agents for Induction of Osteogenic Differentiation in DPSCs and Biomaterial Development Journal Article In: Biomedicines, vol. 13, iss. 12, pp. 3039, 2025. @article{%a1.%Y_248,
title = {CAPE Derivatives as Potent Agents for Induction of Osteogenic Differentiation in DPSCs and Biomaterial Development},
author = {Balaha M and De Filippis B and Rapino M and Kazimierczak P and Przekora A and Esmail T and Toto EC and Petrucci G and Canal C and Cataldi A and di Giacomo V},
url = {https://www.mdpi.com/2227-9059/13/12/3039},
doi = {10.3390/biomedicines13123039},
year = {2025},
date = {2025-12-20},
journal = {Biomedicines},
volume = {13},
issue = {12},
pages = {3039},
abstract = {Objectives: Bone defects, resulting from many causes, represent a challenge in maxillofacial and orthopedic surgery. Regenerative medicine offers promising strategies by introducing exogenous materials to modify the tissue environment and modulate the body's natural healing mechanisms. Dental pulp stem cells (DPSCs) are considered an effective source for tissue repair. Small molecules such as caffeic acid phenethyl ester (CAPE), although having promising effects in promoting bone regeneration, are characterized by low chemical stability, which impairs their clinical application. This study aimed to investigate the bone regenerative capability of four CAPE derivatives, recently synthesized in our laboratory and selected based on previous studies. Methods: DPSCs were induced to osteogenic differentiation in the presence of these compounds (0-5 μM), and cell viability, matrix deposition, alkaline phosphatase activity, and osteogenic marker gene expression were evaluated. In addition, bone biomaterials composed of a chitosan/agarose matrix reinforced with nanohydroxyapatite and enriched with these CAPE derivatives were fabricated and assessed for cytotoxicity and cell adhesion. Results: Two of the tested compounds effectively enhanced DPSC differentiation toward the osteogenic lineage. The fabricated bone biomaterials showed no cytotoxicity and supported cell adhesion. Furthermore, these compounds demonstrated stability under various conditions, confirming their suitability for incorporation into bone biomaterials. Conclusions: The tested CAPE derivatives exhibit promising osteoinductive properties and stability, offering a valid alternative to traditional therapeutic strategies in regenerative medicine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Objectives: Bone defects, resulting from many causes, represent a challenge in maxillofacial and orthopedic surgery. Regenerative medicine offers promising strategies by introducing exogenous materials to modify the tissue environment and modulate the body's natural healing mechanisms. Dental pulp stem cells (DPSCs) are considered an effective source for tissue repair. Small molecules such as caffeic acid phenethyl ester (CAPE), although having promising effects in promoting bone regeneration, are characterized by low chemical stability, which impairs their clinical application. This study aimed to investigate the bone regenerative capability of four CAPE derivatives, recently synthesized in our laboratory and selected based on previous studies. Methods: DPSCs were induced to osteogenic differentiation in the presence of these compounds (0-5 μM), and cell viability, matrix deposition, alkaline phosphatase activity, and osteogenic marker gene expression were evaluated. In addition, bone biomaterials composed of a chitosan/agarose matrix reinforced with nanohydroxyapatite and enriched with these CAPE derivatives were fabricated and assessed for cytotoxicity and cell adhesion. Results: Two of the tested compounds effectively enhanced DPSC differentiation toward the osteogenic lineage. The fabricated bone biomaterials showed no cytotoxicity and supported cell adhesion. Furthermore, these compounds demonstrated stability under various conditions, confirming their suitability for incorporation into bone biomaterials. Conclusions: The tested CAPE derivatives exhibit promising osteoinductive properties and stability, offering a valid alternative to traditional therapeutic strategies in regenerative medicine. |
Esposito F; Capozzo I; Riccardi A; Gioia U; Modafferi S; Manfredi L; Colantoni A; Tavella S; Cabrini M; Iannelli F; di Lillo A; d'Adda di Fagagna F; Francia S DROSHA, DICER, and damage-induced long ncRNA control BMI1-dependent transcriptional repression at DNA double-strand break Journal Article In: Cell reports, vol. 44, iss. 12, pp. 116605, 2025. @article{%a1.%Y,
title = {DROSHA, DICER, and damage-induced long ncRNA control BMI1-dependent transcriptional repression at DNA double-strand break},
author = {Esposito F and Capozzo I and Riccardi A and Gioia U and Modafferi S and Manfredi L and Colantoni A and Tavella S and Cabrini M and Iannelli F and di Lillo A and {d'Adda di Fagagna F} and Francia S},
url = {https://www.sciencedirect.com/science/article/pii/S2211124725013774?via%3Dihub},
doi = {10.1016/j.celrep.2025.116605},
year = {2025},
date = {2025-12-16},
urldate = {2025-12-16},
journal = {Cell reports},
volume = {44},
issue = {12},
pages = {116605},
abstract = {The activation of the DNA-damage response (DDR) enforces the transcriptional silencing of genes near DNA double-strand breaks (DSBs), a process called DSB-induced silencing in cis (DISC). DISC involves the kinase ATM and the polycomb repressive complex 1 (PRC1) component BMI1. Conversely, DSBs also trigger transcription of damage-induced long non-coding RNAs (dilncRNAs) in an MRE11-RAD50-NBS1 (MRN)-complex-dependent manner. MRN recruits the ribonuclease DROSHA, which, along with DICER, enhances DDR signaling and repair. We show that dilncRNAs, DROSHA, and DICER regulate DISC. MRN or ATM inhibition disrupts DISC, while enoxacin, a DICER activator, restores it even without ATM activity. Mechanistically, DROSHA and DICER enable BMI1 recruitment and H2A-K119 ubiquitination at DSBs. BMI1 interacts with DROSHA and dilncRNAs in a DICER-dependent manner. Blocking dilncRNAs by antisense oligonucleotide and Cas13 reduces BMI1 recruitment and DISC. We propose that DROSHA, DICER, and dilncRNAs mediate DISC by promoting PRC1 recruitment and chromatin modification at DSBs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The activation of the DNA-damage response (DDR) enforces the transcriptional silencing of genes near DNA double-strand breaks (DSBs), a process called DSB-induced silencing in cis (DISC). DISC involves the kinase ATM and the polycomb repressive complex 1 (PRC1) component BMI1. Conversely, DSBs also trigger transcription of damage-induced long non-coding RNAs (dilncRNAs) in an MRE11-RAD50-NBS1 (MRN)-complex-dependent manner. MRN recruits the ribonuclease DROSHA, which, along with DICER, enhances DDR signaling and repair. We show that dilncRNAs, DROSHA, and DICER regulate DISC. MRN or ATM inhibition disrupts DISC, while enoxacin, a DICER activator, restores it even without ATM activity. Mechanistically, DROSHA and DICER enable BMI1 recruitment and H2A-K119 ubiquitination at DSBs. BMI1 interacts with DROSHA and dilncRNAs in a DICER-dependent manner. Blocking dilncRNAs by antisense oligonucleotide and Cas13 reduces BMI1 recruitment and DISC. We propose that DROSHA, DICER, and dilncRNAs mediate DISC by promoting PRC1 recruitment and chromatin modification at DSBs. |
Weiss BL; Gstöttenmayer F; Awuoche E; Smallenberger GM; Attardo GM; Scolari F; Koch RT; Bruzzese DJ; Echodu R; Opiro R; Malacrida A; Abd-Alla AMM; Aksoy S Endosymbiont hijacking of acylcarnitines regulates insect vector fecundity by suppressing the viability of stored sperm Journal Article In: PLoS genetics, vol. 21, iss. 12, pp. e1011974, 2025. @article{%a1.%Y_250,
title = {Endosymbiont hijacking of acylcarnitines regulates insect vector fecundity by suppressing the viability of stored sperm},
author = {Weiss BL and Gstöttenmayer F and Awuoche E and Smallenberger GM and Attardo GM and Scolari F and Koch RT and Bruzzese DJ and Echodu R and Opiro R and Malacrida A and Abd-Alla AMM and Aksoy S},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1011974},
doi = {10.1371/journal.pgen.1011974},
year = {2025},
date = {2025-12-16},
journal = {PLoS genetics},
volume = {21},
issue = {12},
pages = {e1011974},
abstract = {Competition between insects and their endosymbiotic bacteria for environmentally limited nutrients can compromise the fitness of both organisms. Tsetse flies, the vectors of pathogenic African trypanosomes, harbor a species and population-specific consortium of vertically transmitted endosymbiotic bacteria that range on the functional spectrum from mutualistic to parasitic. Tsetse's indigenous microbiota can include a member of the genus Spiroplasma, and infection with this bacterium causes fecundity-reducing phenotypes in the fly that include a prolonged gonotrophic cycle and a reduction in the motility of stored spermatozoa post-copulation. Herein we demonstrate that Spiroplasma and tsetse spermatozoa compete for fly-derived acylcarnitines, which in other bacteria and animals are used to maintain cell membranes and produce energy. The fat body of mated female flies increases acylcarnitine production in response to infection with Spiroplasma. Additionally, their spermathecae (sperm storage organs), and likely the sperm within, up-regulate expression of carnitine O-palmitoyltransferase-1, which is indicative of increased acylcarnitine metabolism and thus increased energy demand and energy production in this organ. These compensatory measures are insufficient to rescue the motility defect of spermatozoa stored in the spermathecae of Spiroplasma-infected females and thus results in reduced fly fecundity. Tsetse's taxonomically simple and highly tractable indigenous microbiota make the fly an efficient model system for studying the biological processes that facilitate the maintenance of bacterial endosymbioses, and how these relationships impact conserved mechanisms (mammalian spermatozoa also use acylcarnitines as an energy source) that regulated animal host fecundity. In the case of insect pests and vectors, a better understanding of the metabolic mechanisms that underlie these associations can lead to the development of novel control strategies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Competition between insects and their endosymbiotic bacteria for environmentally limited nutrients can compromise the fitness of both organisms. Tsetse flies, the vectors of pathogenic African trypanosomes, harbor a species and population-specific consortium of vertically transmitted endosymbiotic bacteria that range on the functional spectrum from mutualistic to parasitic. Tsetse's indigenous microbiota can include a member of the genus Spiroplasma, and infection with this bacterium causes fecundity-reducing phenotypes in the fly that include a prolonged gonotrophic cycle and a reduction in the motility of stored spermatozoa post-copulation. Herein we demonstrate that Spiroplasma and tsetse spermatozoa compete for fly-derived acylcarnitines, which in other bacteria and animals are used to maintain cell membranes and produce energy. The fat body of mated female flies increases acylcarnitine production in response to infection with Spiroplasma. Additionally, their spermathecae (sperm storage organs), and likely the sperm within, up-regulate expression of carnitine O-palmitoyltransferase-1, which is indicative of increased acylcarnitine metabolism and thus increased energy demand and energy production in this organ. These compensatory measures are insufficient to rescue the motility defect of spermatozoa stored in the spermathecae of Spiroplasma-infected females and thus results in reduced fly fecundity. Tsetse's taxonomically simple and highly tractable indigenous microbiota make the fly an efficient model system for studying the biological processes that facilitate the maintenance of bacterial endosymbioses, and how these relationships impact conserved mechanisms (mammalian spermatozoa also use acylcarnitines as an energy source) that regulated animal host fecundity. In the case of insect pests and vectors, a better understanding of the metabolic mechanisms that underlie these associations can lead to the development of novel control strategies. |
Vignoli D; Albertini M; Chiatti C; Aimaretti G; Boccuzzo G; Boffo V; Brugiavini A; Cavallo F; Cenci S; Cherubini A; Cincotti F; d'Adda di Fagagna F; Ferrarese C; Galasso V; Galeotti E; Graziani A; Iaccarino G; Lattanzio F; Lucifora C; Mezzanzanica M; Passarino G; Paterno A; Prati S; Rumiati RI; Sandri M; Tomassini C; Torbica A; Ungar A; Petrucci A Aging well in an aging society: Italy at the forefront of global aging and the Age-It Research Program Journal Article In: Journals of gerontology. Series B, Psychological sciences and social sciences, vol. 80, iss. suppl. 2, pp. S99-S109, 2025. @article{%a1.%Y,
title = {Aging well in an aging society: Italy at the forefront of global aging and the Age-It Research Program},
author = {Vignoli D and Albertini M and Chiatti C and Aimaretti G and Boccuzzo G and Boffo V and Brugiavini A and Cavallo F and Cenci S and Cherubini A and Cincotti F and {d'Adda di Fagagna F} and Ferrarese C and Galasso V and Galeotti E and Graziani A and Iaccarino G and Lattanzio F and Lucifora C and Mezzanzanica M and Passarino G and Paterno A and Prati S and Rumiati RI and Sandri M and Tomassini C and Torbica A and Ungar A and Petrucci A},
url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC12736989/},
doi = {10.1093/geronb/gbaf219},
year = {2025},
date = {2025-12-16},
urldate = {2025-12-16},
journal = {Journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {80},
issue = {suppl. 2},
pages = {S99-S109},
abstract = {Objectives: Italy, one of the world's super-aged societies, faces profound demographic transformations amid relevant regional disparities in sociodemographic trends, institutional structures, and economic conditions. These features make it an ideal laboratory to study both the challenges and opportunities of population aging. This article introduces Age-It, a Research Program designed to leverage Italy's position at the forefront of global aging to advance transdisciplinary research and inform evidence-based policies and practices on aging. Methods: Age-It adopts a life course perspective encompassing individual, family, and societal levels. It conceptualizes "aging well" as the outcome of multi-agent, multi-context processes unfolding from early life through old age. Furthermore, Age-It moves beyond a multidisciplinary approach by fostering true cross-fertilization between biomedical, sociodemographic, and technological sciences. Structured as an umbrella initiative, the program brings together multiple interlinked projects that address diverse dimensions of aging through transdisciplinary and collaborative research. Results: The program addresses key limitations in Italy's current aging research and policy landscape: fragmented data, disciplinary silos, and weak connections between research and policymaking. By integrating biomedical, technological, and socioeconomic perspectives into structured, theory-driven research centers (Spokes), Age-It provides a coordinated and innovative platform for studying aging. Discussion: Leveraging Italy's unique demographic profile and internal heterogeneity, Age-It promotes sustainable aging by harnessing the opportunities embedded in demographic change. The program ranges from the biology of aging to mental and physical health prevention, long-term care, labor market dynamics, and social participation-ultimately aiming to reshape how aging is perceived and managed in aging societies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Objectives: Italy, one of the world's super-aged societies, faces profound demographic transformations amid relevant regional disparities in sociodemographic trends, institutional structures, and economic conditions. These features make it an ideal laboratory to study both the challenges and opportunities of population aging. This article introduces Age-It, a Research Program designed to leverage Italy's position at the forefront of global aging to advance transdisciplinary research and inform evidence-based policies and practices on aging. Methods: Age-It adopts a life course perspective encompassing individual, family, and societal levels. It conceptualizes "aging well" as the outcome of multi-agent, multi-context processes unfolding from early life through old age. Furthermore, Age-It moves beyond a multidisciplinary approach by fostering true cross-fertilization between biomedical, sociodemographic, and technological sciences. Structured as an umbrella initiative, the program brings together multiple interlinked projects that address diverse dimensions of aging through transdisciplinary and collaborative research. Results: The program addresses key limitations in Italy's current aging research and policy landscape: fragmented data, disciplinary silos, and weak connections between research and policymaking. By integrating biomedical, technological, and socioeconomic perspectives into structured, theory-driven research centers (Spokes), Age-It provides a coordinated and innovative platform for studying aging. Discussion: Leveraging Italy's unique demographic profile and internal heterogeneity, Age-It promotes sustainable aging by harnessing the opportunities embedded in demographic change. The program ranges from the biology of aging to mental and physical health prevention, long-term care, labor market dynamics, and social participation-ultimately aiming to reshape how aging is perceived and managed in aging societies. |
Sabatell P; Di Martino A; Faldini C; Bonaldo P; Merlini L; Cenni V Tendon Dysfunction in Collagen VI-Related Myopathies: Novel Mechanistic Insights with Therapeutic Potential Journal Article In: International journal of molecular sciences, vol. 26, iss. 24, pp. 12014, 2025. @article{%a1.%Y_249,
title = {Tendon Dysfunction in Collagen VI-Related Myopathies: Novel Mechanistic Insights with Therapeutic Potential},
author = {Sabatell P and Di Martino A and Faldini C and Bonaldo P and Merlini L and Cenni V},
url = {https://www.mdpi.com/1422-0067/26/24/12014},
doi = {10.3390/ijms262412014},
year = {2025},
date = {2025-12-16},
journal = {International journal of molecular sciences},
volume = {26},
issue = {24},
pages = {12014},
abstract = {Collagen VI-related myopathies (COL6-RM) encompass a spectrum of disorders characterized by muscle weakness, joint contractures, and connective tissue abnormalities resulting from mutations in the collagen VI genes. While muscle pathology has been extensively studied, tendon dysfunction has emerged as a critical yet underexplored contributor to disease severity, particularly in the development of joint contractures. Tendons from patients and animal models show disrupted collagen fibrillogenesis, altered extracellular matrix (ECM) composition, and impaired cellular mechanotransduction. Various defects in ECM remodeling pathways further exacerbate tendon pathology. Importantly, current clinical management remains limited to orthopedic interventions with modest outcomes, and targeted pharmacological strategies or gene-editing therapies are not yet available for clinical application. Therefore, understanding the basic pathogenic mechanisms underlying tendon dysfunction is essential for identifying novel therapeutic targets. This review provides a comprehensive synthesis of current understanding and recent advances concerning the role of mutated collagen VI in cellular and molecular mechanisms underlying tendon dysfunction. Emphasis is placed on the role of mutated collagen VI in the modulation of key signaling pathways related to mechanotransduction and primary cilium function in COL6-RM. By discussing these multifaceted contributions to disease pathogenesis, this review outlines future research directions in the field and highlights potential pathways for targeted therapeutic interventions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Collagen VI-related myopathies (COL6-RM) encompass a spectrum of disorders characterized by muscle weakness, joint contractures, and connective tissue abnormalities resulting from mutations in the collagen VI genes. While muscle pathology has been extensively studied, tendon dysfunction has emerged as a critical yet underexplored contributor to disease severity, particularly in the development of joint contractures. Tendons from patients and animal models show disrupted collagen fibrillogenesis, altered extracellular matrix (ECM) composition, and impaired cellular mechanotransduction. Various defects in ECM remodeling pathways further exacerbate tendon pathology. Importantly, current clinical management remains limited to orthopedic interventions with modest outcomes, and targeted pharmacological strategies or gene-editing therapies are not yet available for clinical application. Therefore, understanding the basic pathogenic mechanisms underlying tendon dysfunction is essential for identifying novel therapeutic targets. This review provides a comprehensive synthesis of current understanding and recent advances concerning the role of mutated collagen VI in cellular and molecular mechanisms underlying tendon dysfunction. Emphasis is placed on the role of mutated collagen VI in the modulation of key signaling pathways related to mechanotransduction and primary cilium function in COL6-RM. By discussing these multifaceted contributions to disease pathogenesis, this review outlines future research directions in the field and highlights potential pathways for targeted therapeutic interventions. |
Lauriola A; Enrique Steinberg JH; Sarubo M; Maspero E; Rossi FA; Mouri Y; Pedretti M; Hajisadeghian M; Taibi V; Vettori A; Vitulo N; Assfalg M; D'Onofrio M; Rossi M; Yasue A; Astegno A; Polo S; Santi S; Kudo Y; Guardavaccaro D
The E3 ligase RNF32 controls the IκB kinase complex and NF-κB signaling in intestinal stem cells Journal Article In: Molecular cell, vol. 85, iss. 22, pp. 4254-4267, 2025. @article{%a1.%Y_246,
title = {The E3 ligase RNF32 controls the IκB kinase complex and NF-κB signaling in intestinal stem cells},
author = {Lauriola A and Enrique Steinberg JH and Sarubo M and Maspero E and Rossi FA and Mouri Y and Pedretti M and Hajisadeghian M and Taibi V and Vettori A and Vitulo N and Assfalg M and D'Onofrio M and Rossi M and Yasue A and Astegno A and Polo S and Santi S and Kudo Y and Guardavaccaro D
},
url = {https://www.sciencedirect.com/science/article/pii/S1097276525008226?via%3Dihub},
doi = {10.1016/j.molcel.2025.10.005},
year = {2025},
date = {2025-11-19},
urldate = {2025-11-19},
journal = {Molecular cell},
volume = {85},
issue = {22},
pages = {4254-4267},
abstract = {Nuclear factor κB (NF-κB) signaling is a central pathway regulating a plethora of cellular functions. Here, we find that RNF32, a RING E3 ubiquitin ligase whose expression is enriched in murine intestinal stem cells, regulates the activity of the IκB kinase (IKK) complex, the signal integration hub for NF-κB activation. The E3 ligase activity of RNF32 depends on calmodulin, the primary calcium sensor in eukaryotic cells. Increased levels of intracellular calcium ion (Ca2+) induce RNF32 binding to calmodulin, RNF32 activation, and autoubiquitylation. In turn, polyubiquitin chains conjugated to RNF32 recruit NEMO, the regulatory subunit of the IKK complex. Moreover, Ca2+ rise triggers RNF32 phase separation, which is required for the formation of NEMO condensates and IKK activation. Finally, we show that RNF32 is required for NF-κB activation triggered by bacterial lipopolysaccharides. Collectively, our findings uncover a mechanism controlling NF-κB signaling in the intestinal epithelium.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Nuclear factor κB (NF-κB) signaling is a central pathway regulating a plethora of cellular functions. Here, we find that RNF32, a RING E3 ubiquitin ligase whose expression is enriched in murine intestinal stem cells, regulates the activity of the IκB kinase (IKK) complex, the signal integration hub for NF-κB activation. The E3 ligase activity of RNF32 depends on calmodulin, the primary calcium sensor in eukaryotic cells. Increased levels of intracellular calcium ion (Ca2+) induce RNF32 binding to calmodulin, RNF32 activation, and autoubiquitylation. In turn, polyubiquitin chains conjugated to RNF32 recruit NEMO, the regulatory subunit of the IKK complex. Moreover, Ca2+ rise triggers RNF32 phase separation, which is required for the formation of NEMO condensates and IKK activation. Finally, we show that RNF32 is required for NF-κB activation triggered by bacterial lipopolysaccharides. Collectively, our findings uncover a mechanism controlling NF-κB signaling in the intestinal epithelium. |
Broseghini E, Fontana B, Durante G, Roncarati R, Ferracin M Quantification of Tissue and Circulating MicroRNAs by Droplet Digital PCR Book Chapter In: vol. 12969, pp. 195-233, Humana Press New York, Digital PCR ed. Pavlovic G, 2025. @inbook{%a1.%Y_245,
title = {Quantification of Tissue and Circulating MicroRNAs by Droplet Digital PCR},
author = {Broseghini E, Fontana B, Durante G, Roncarati R, Ferracin M},
url = {https://link.springer.com/protocol/10.1007/978-1-0716-4767-7_13},
doi = {10.1007/978-1-0716-4767-7_13},
year = {2025},
date = {2025-11-19},
volume = {12969},
pages = {195-233},
publisher = {Humana Press New York},
edition = {Digital PCR ed. Pavlovic G},
series = {Methods in molecular biology},
abstract = {MicroRNAs (miRNAs) are gene expression regulators that play a fundamental role in developmental and biological processes. Dysregulated expression of miRNAs has been associated with most human conditions, and their accurate quantification is an essential activity in molecular biology laboratories. Indeed, the levels of specific tissue or circulating miRNAs have been tested as disease biomarkers in many clinical and experimental settings. Droplet digital PCR (ddPCR) technology is a sensitive and accurate method to obtain the absolute or relative quantification of specific miRNAs, bypassing several issues related to low abundance targets and PCR efficiency. This chapter addresses the workflow and methods for miRNA quantification in formalin-fixed paraffin-embedded (FFPE) samples, cells, and plasma/serum/extracellular vesicles using EvaGreen-based ddPCR or probe-based ddPCR, as well as how to analyze and interpret results. In addition, we provide a ddPCR method to quantify miRNA isoforms (isomiRs).},
keywords = {},
pubstate = {published},
tppubtype = {inbook}
}
MicroRNAs (miRNAs) are gene expression regulators that play a fundamental role in developmental and biological processes. Dysregulated expression of miRNAs has been associated with most human conditions, and their accurate quantification is an essential activity in molecular biology laboratories. Indeed, the levels of specific tissue or circulating miRNAs have been tested as disease biomarkers in many clinical and experimental settings. Droplet digital PCR (ddPCR) technology is a sensitive and accurate method to obtain the absolute or relative quantification of specific miRNAs, bypassing several issues related to low abundance targets and PCR efficiency. This chapter addresses the workflow and methods for miRNA quantification in formalin-fixed paraffin-embedded (FFPE) samples, cells, and plasma/serum/extracellular vesicles using EvaGreen-based ddPCR or probe-based ddPCR, as well as how to analyze and interpret results. In addition, we provide a ddPCR method to quantify miRNA isoforms (isomiRs). |
