@article{%a1.%Y_214,

title = {Trichothiodystrophy-causative pathogenic variants impair a cooperative action of TFIIH and DDX1 in R-loop processing},

author = {Ferri D and Branca G and Lanzafame M and Gandolfi E and Riva V and Maga G and Nardo T and Landi C and Bini L and Arseni L and Peverali FA and Compe E and Orioli D},

url = {https://academic.oup.com/nar/article/53/14/gkaf745/8221718?login=true},

doi = {10.1093/nar/gkaf745},

year  = {2025},

date = {2025-08-11},

journal = {Nucleic Acids Research},

volume = {53},

issue = {14},

pages = {gkaf745},

abstract = {The transcription factor IIH (TFIIH) is a key player in transcription and DNA repair by nucleotide excision repair. It is made of 10 subunits organized in core-TFIIH and CAK sub-complexes bridged by XPD. Pathogenic variants in the ERCC2/XPD gene give rise to xeroderma pigmentosum (XP) or trichothiodystrophy (TTD), two distinct clinical entities with opposite skin cancer proneness. Here, we show that TTD variants cause a partial dissociation of the CAK from the chromatin and from the core-TFIIH. Mass spectrometry analysis reveals that the chromatin-bound CAK, as a component of the entire TFIIH, participates in a protein assembly containing the RNA-binding proteins DDX1, SFPQ, NONO as well as RNA polymerase II (Pol II). Gene silencing experiments demonstrate that the protein assembly is required to process the DNA:RNA hybrids formed during Pol II extension and to protect the cell from transcriptional stress. TTD-specific variants in ERCC2/XPD result in TFIIH instability, altered interaction of the CAK with DDX1-SFPQ-NONO, and R-loop accumulation. Therefore, the limited amount of TFIIH that distinguishes TTD from XP gives rise to transcriptional stress and extensive gene expression deregulations, thus accounting for the wide spectrum of TTD clinical features.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Trichothiodystrophy: Molecular insights and mechanisms of pathogenicity},

author = {Lanzafame M and Brevi F and Veniali G and Botta E},

url = {https://www.sciencedirect.com/science/article/pii/S1383574225000262?via%3Dihub},

doi = {10.1016/j.mrrev.2025.108555},

year  = {2025},

date = {2025-08-11},

journal = {Mutation research. Reviews in mutation research},

abstract = {Trichothiodystrophy (TTD) is a rare hereditary disease characterized by brittle, sulphur deficient hair associated with a wide and varied spectrum of clinical features which include skin alterations, neurodevelopmental defects, and immune dysfunction. The presence of hypersensitivity to UV light defines the two main forms of TTD: photosensitive (PS-TTD) and non-photosensitive (NPS-TTD). The disease arises from mutations in a variety of genes involved in different biological processes. Affected processes include DNA repair, transcription as well as translation. This review provides the latest vision of TTD: from up-to-date mutational spectra and genotype-phenotype relationships to our current understanding of the pathogenic mechanisms that underlie the complex etiology of this multi-faceted disease.},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{%a1.%Yb_56,

title = {TFIIH stabilization recovers the DNA repair and transcription dysfunctions in thermo-sensitive trichothiodystrophy},

author = {Lanzafame M and Nardo T and Ricotti R and Pantaleoni C and D'Arrigo S and Stanzial F and Benedicenti F and Thomas MA and Stefanini M and Orioli D and Botta E},

url = {https://onlinelibrary.wiley.com/doi/10.1002/humu.24488},

doi = {10.1002/humu.24488},

year  = {2022},

date = {2022-03-25},

journal = {Human mutation},

volume = {43},

issue = {12},

pages = {2222},

abstract = {Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. The photosensitive form of TTD (PS-TTD) is most commonly caused by mutations in the ERCC2/XPD gene encoding a subunit of the transcription/DNA repair complex TFIIH. Here we report novel ERCC2/XPD mutations affecting proper protein folding, which generate thermo-labile forms of XPD associated with thermo-sensitive phenotypes characterized by reversible aggravation of TTD clinical signs during episodes of fever. In patient cells, the newly identified XPD variants result in thermo-instability of the whole TFIIH complex and consequent temperature-dependent defects in DNA repair and transcription. Improving the protein folding process by exposing patient cells to low temperature or to the chemical chaperone glycerol allowed rescue of TFIIH thermo-instability and a concomitant recovery of the complex activities. Besides providing a rationale for the peculiar thermo-sensitive clinical features of these new cases, the present findings demonstrate how variations in the cellular concentration of mutated TFIIH impact the cellular functions of the complex and underlie how both quantitative and qualitative TFIIH alterations contribute to TTD clinical features.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Ybvz,

title = {Cockayne syndrome group A and ferrochelatase finely tune ribosomal gene transcription and its response to UV irradiation},

author = {Lanzafame M and Branca G and Landi C and Qiang M and Vaz B and Nardo T and Ferri D and Mura M and Iben S and Stefanini M and Peverali FA and Bini L and Orioli D},

url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkab819/6377400},

doi = {10.1093/nar/gkab819},

year  = {2021},

date = {2021-10-28},

urldate = {2021-10-28},

journal = {Nucleic Acids Research},

volume = {49},

number = {10911},

issue = {19},

pages = {10930},

abstract = {CSA and CSB proteins are key players in transcription-coupled nucleotide excision repair (TC-NER) pathway that removes UV-induced DNA lesions from the transcribed strands of expressed genes. Additionally, CS proteins play relevant but still elusive roles in other cellular pathways whose alteration may explain neurodegeneration and progeroid features in Cockayne syndrome (CS). Here we identify a CS-containing chromatin-associated protein complex that modulates rRNA transcription. Besides RNA polymerase I (RNAP1) and specific ribosomal proteins (RPs), the complex includes ferrochelatase (FECH), a well-known mitochondrial enzyme whose deficiency causes erythropoietic protoporphyria (EPP). Impairment of either CSA or FECH functionality leads to reduced RNAP1 occupancy on rDNA promoter that is associated to reduced 47S pre-rRNA transcription. In addition, reduced FECH expression leads to an abnormal accumulation of 18S rRNA that in primary dermal fibroblasts from CS and EPP patients results in opposed rRNA amounts. After cell irradiation with UV light, CSA triggers the dissociation of the CSA-FECH-CSB-RNAP1-RPs complex from the chromatin while it stabilizes its binding to FECH. Besides disclosing a function for FECH within nucleoli, this study sheds light on the still unknown mechanisms through which CSA modulates rRNA transcription.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_81,

title = {Non-viral gene delivery of the oncotoxic protein NS1 for treatment of hepatocellular carcinoma},

author = {Witzigmann D and Grossen P and Quintavalle C and Lanzafame M and Schenk SH and Tran XT and Englinger B and Hauswirth P and Grunig D and van Schoonhoven S and Krahenbuhl S and Terracciano LM and Berger W and Piscuoglio S and Quagliata L and Rommelaere J and Nuesch JPF and Huwyler J},

url = {https://www.sciencedirect.com/science/article/pii/S0168365921001899?via%3Dihub},

doi = {10.1016/j.jconrel.2021.04.023},

year  = {2021},

date = {2021-06-23},

journal = {J Control Release},

volume = {334},

pages = {138-152},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_79,

title = {Systematic identification of novel cancer genes through analysis of deep shRNA perturbation screens},

author = {Montazeri H and Coto-Llerena M and Bianco G and Zangene E and Taha-Mehlitz S and Paradiso V and Srivatsa S and {de Weck A} and Roma G and Lanzafame M and Bolli M and Beerenwinkel N and {von Flue M} and Terracciano LM and Piscuoglio S and Ng CKY},

url = {https://academic.oup.com/nar/article/49/15/8488/6329117},

doi = {doi: 10.1093/nar/gkab62},

year  = {2021},

date = {2021-09-07},

journal = {Nucleic acids research},

volume = {49},

issue = {15},

pages = {8488-8504},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_80,

title = {The polyphenol/saponin-rich Rhus tripartita extract has an apoptotic effect on THP-1 cells through the PI3K/AKT/mTOR signaling pathway},

author = {Tlili H and Macovei A and Buonocore D and Lanzafame M and Najjaa H and Lombardi A and Pagano A and Dossena M and Verri M and Arfa AB and Neffati M and Doria E},

url = {https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-021-03328-9},

doi = {10.1186/s12906-021-03328-9},

year  = {2021},

date = {2021-05-21},

journal = {BMC Complement Med Ther},

volume = {21},

issue = {1},

pages = {153},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_82,

title = {Prevention of dsRNA-induced interferon signaling by AGO1x is linked to breast cancer cell proliferation},

author = {Ghosh S and Guimaraes JC and Lanzafame M and Schmidt A and Syed AP and Dimitriades B and Börsch A and Ghosh S and Mittal N and Montavon T and Correia AL and Danner J and Meister G and Terracciano LM and Pfeffer S and Piscuoglio S and Zavolan M},

url = {https://www.embopress.org/doi/full/10.15252/embj.2019103922},

doi = {10.15252/embj.2019103922},

year  = {2020},

date = {2020-09-15},

journal = {EMBO Journal},

volume = {39},

issue = {18},

pages = {e103922},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_83,

title = {Novel biomarkers for primary biliary cholangitis to improve diagnosis and understand underlying regulatory mechanisms.},

author = {Bombaci M and Pesce E and Torri A and Carpi D and Crosti M and Lanzafame M and Cordiglieri C and Sinisi A and Moro M and Bernuzzi F and Gerussi A and Geginat J and Muratori L and Terracciano LM and Invernizzi P and Abrignani S and Grifantini R },

url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/liv.14128},

doi = {10.1111/liv.14128},

year  = {2019},

date = {2019-03-30},

journal = {Liver Int},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_84,

title = {Diagnostic targeted sequencing panel for hepatocellular carcinoma genomic screening},

author = {Paradiso V and Garofoli A and Tosti N and Lanzafame M and Perrina V and Quagliata L and Matter MS and Wieland S and Heim MH and Piscuoglio S and Ng CKY and Terracciano LM },

url = {https://www.sciencedirect.com/science/article/pii/S1525157818300254},

doi = {10.1016/j.jmoldx.2018.07.003},

year  = {2018},

date = {2018-03-31},

journal = {J Mol Diagn},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_122,

title = {Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome.},

author = {Calmels N and Botta E and Jia N and Fawcett H and Nardo T and Nakazawa Y and Lanzafame M and Moriwaki S and Sugita K and Kubota M and Obringer C and Spitz MA and Stefanini M and Laugel V and Orioli D and Ogi T and Lehmann AR},

url = {https://jmg.bmj.com/content/55/5/329.long},

doi = {10.1136/jmedgenet-2017-104877},

year  = {2018},

date = {2018-05-31},

journal = {Journal of medical genetics},

volume = {55},

number = {5},

pages = {329-343},

abstract = {BACKGROUND: Cockayne syndrome (CS) is a rare, autosomal recessive multisystem disorder characterised by prenatal or postnatal growth failure, progressive neurological dysfunction, ocular and skeletal abnormalities and premature ageing. About half of the patients with symptoms diagnostic for CS show cutaneous photosensitivity and an abnormal cellular response to UV light due to mutations in either the ERCC8/CSA or ERCC6/CSB gene. Studies performed thus far have failed to delineate clear genotype-phenotype relationships. We have carried out a four-centre clinical, molecular and cellular analysis of 124 patients with CS. METHODS AND RESULTS: We assigned 39 patients to the ERCC8/CSA and 85 to the ERCC6/CSB genes. Most of the genetic variants were truncations. The missense variants were distributed non-randomly with concentrations in relatively short regions of the respective proteins. Our analyses revealed several hotspots and founder mutations in ERCC6/CSB. Although no unequivocal genotype-phenotype relationships could be made, patients were more likely to have severe clinical features if the mutation was downstream of the PiggyBac insertion in intron 5 of ERCC6/CSB than if it was upstream. Also a higher proportion of severely affected patients was found with mutations in ERCC6/CSB than in ERCC8/CSA. CONCLUSION: By identifying >70 novel homozygous or compound heterozygous genetic variants in 124 patients with CS with different disease severity and ethnic backgrounds, we considerably broaden the CSA and CSB mutation spectrum responsible for CS. Besides providing information relevant for diagnosis of and genetic counselling for this devastating disorder, this study improves the definition of the puzzling genotype-phenotype relationships in patients with CS.

Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_85,

title = {Genetic profiling using plasma-derived cell-free DNA in therapy-naïve hepatocellular carcinoma patients: a pilot study},

author = {Ng CKY and Di Costanzo GG and Tosti N and Paradiso V and Coto-Llerena M and Roscigno G and Perrina V and Quintavalle C and Boldanova T and Wieland S and Marino-Marsilia G and Lanzafame M and Quagliata L and Condorelli G and Matter MS and Tortora R and Heim MH and Terracciano LM and Piscuoglio S },

url = {https://www.sciencedirect.com/science/article/pii/S092375341934548X},

doi = {10.1093/annonc/mdy083},

year  = {2018},

date = {2018-03-30},

journal = {Ann Oncol },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_86,

title = {Genomic Analysis Revealed New Oncogenic Signatures in TP53-Mutant Hepatocellular Carcinoma.},

author = {Kancherla V and Abdullazade S and Matter MS and Lanzafame M and Quagliata L and Roma G and Hoshida Y and Terracciano LM and Ng CKY and Piscuoglio S },

url = {https://www.frontiersin.org/articles/10.3389/fgene.2018.00002/full},

doi = {10.3389/fgene.2018.00002},

year  = {2018},

date = {2018-03-30},

journal = {Front Genet},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_87,

title = {High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models.},

author = {Quagliata L and Quintavalle C and Lanzafame M and Matter MS and Novello C and di Tommaso L and Pressiani T and Rimassa L and Tornillo L and Roncalli M and Cillo C and Pallante P and Piscuoglio S and Ng CK and Terracciano LM },

url = {https://www.nature.com/articles/labinvest2017107},

doi = {10.1038/labinvest.2017.107},

year  = {2018},

date = {2018-03-29},

journal = {Lab Invenst},

volume = {98},

pages = {95-10},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_290,

title = {GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy.},

author = {Kuschal C and Botta E and Orioli D and Digiovanna JJ and Seneca S and Keymolen K and Tamura D and Heller E and Khan SG and Caligiuri G and Lanzafame M and Nardo T and Ricotti R and Peverali FA and Stephens R and Zhao Y and Lehmann AR and Baranello L and Levens D and Kraemer KH and Stefanini M},

url = {http://www.sciencedirect.com/science/article/pii/S0002929716000598},

doi = {10.1016/j.ajhg.2016.02.008},

year  = {2016},

date = {2016-04-16},

journal = {American Journal of Human Genetics},

volume = {98},

number = {4},

pages = {627-642},

abstract = {The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEbeta). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEalpha and TFIIEbeta) as well as decreased phosphorylation of TFIIEalpha in cells from both children. Interestingly, decreased phosphorylation of TFIIEalpha was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP. Copyright  2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_303,

title = {Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells},

author = {Pascucci B and D'Errico M and Romagnoli A and De Nuccio C and Savino M and Pietraforte D and Lanzafame M and Calcagnile AS and Fortini P and Baccarini S and Orioli D and Degan P and Visentin S and Stefanini M and Isidoro C and Fimia GM and Dogliotti E},

url = {http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=9913&pubmed-linkout=1},

doi = {10.18632/oncotarget.9913},

year  = {2016},

date = {2016-06-07},

journal = {Oncotarget},

volume = {8},

number = {61},

pages = {102852-102867},

abstract = {The ERCC8/CSA gene encodes a WD-40 repeat protein (CSA) that is part of a E3-ubiquitin ligase/COP9 signalosome complex. When mutated, CSA causes the Cockayne Syndrome group A (CS-A), a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells features include ROS hyperproduction, accumulation of oxidative genome damage, mitochondrial dysfunction and increased apoptosis that may contribute to the neurodegenerative process. In this study, we show that CSA localizes to mitochondria and specifically interacts with the mitochondrial fission protein dynamin-related protein (DRP1) that is hyperactivated when CSA is defective. Increased fission is not counterbalanced by increased mitophagy in CS-A cells thus leading to accumulation of fragmented mitochondria. However, when mitochondria are challenged with the mitochondrial toxin carbonyl cyanide m-chloro phenyl hydrazine, CS-A fibroblasts undergo mitophagy as efficiently as normal fibroblasts, suggesting that this process remains targetable to get rid of damaged mitochondria. Indeed, when basal mitophagy was potentiated by overexpressing Parkin in CSA deficient cells, a significant rescue of the dysfunctional mitochondrial phenotype was observed. Importantly, Parkin overexpression not only reactivates basal mitophagy, but plays also an anti-apoptotic role by significantly reducing the translocation of Bax at mitochondria in CS-A cells. These findings provide new mechanistic insights into the role of CSA in mitochondrial maintenance and might open new perspectives for therapeutic approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_400,

title = {Reference genes for gene expression analysis in proliferating and differentiating human keratinocytes.},

author = {Lanzafame M and Botta E and Teson M and Fortugno P and Zambruno G and Stefanini M and Orioli D},

url = {https://iubmb.onlinelibrary.wiley.com/doi/full/10.1002/iub.1366},

doi = {10.1002/iub.1366},

year  = {2015},

date = {2015-04-07},

journal = {Experimental Dermatology},

volume = {24},

number = {4},

abstract = {Abnormalities in keratinocyte growth and differentiation have a pathogenic significance in many skin disorders and result in gene expression alterations detectable by quantitative real-time RT-PCR (qRT-PCR). Relative quantification based on endogenous control (EC) genes is the commonly adopted approach, and the use of multiple reference genes from independent pathways is considered a best practice guideline, unless fully validated EC genes are available. The literature on optimal reference genes during in vitro calcium-induced differentiation of normal human epidermal keratinocytes (NHEK) is inconsistent. In many studies, the expression of target genes is compared to that of housekeeping genes whose expression, however, significantly varies during keratinocyte differentiation. Here, we report the results of our investigations on the expression stability of 15 candidate EC genes, including those commonly used as reference in expression analysis by qRT-PCR, during NHEK calcium-induced differentiation. We demonstrate that YWHAZ and UBC are extremely stable genes, and therefore, they represent optimal EC genes for expression studies in proliferating and calcium-induced differentiating NHEK. Furthermore, we demonstrate that YWHAZ/14-3-3-zeta is a suitable reference for quantitative comparison of both transcript and protein levels. 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_409,

title = {TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin.},

author = {Arseni L and Lanzafame M and Compe E and Fortugno P and Afonso-Barroso A and Peverali FA and Lehmann AR and Zambruno G and Egly JM and Stefanini M and Orioli D},

url = {https://www.pnas.org/content/112/5/1499.long},

doi = {10.1073/pnas.1416181112},

year  = {2015},

date = {2015-02-03},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {112},

number = {5},

pages = {1499-1504},

abstract = {Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in distinct clinical entities, including the cancer-prone xeroderma pigmentosum (XP) and the multisystem disorder trichothiodystrophy (TTD), which share only cutaneous photosensitivity. Gene-expression profiles of primary dermal fibroblasts revealed overexpression of matrix metalloproteinase 1 (MMP-1), the gene encoding the metalloproteinase that degrades the interstitial collagens of the extracellular matrix (ECM), in TTD patients mutated in XPD compared with their healthy parents. The defect is observed in TTD and not in XP and is specific for fibroblasts, which are the main producers of dermal ECM. MMP-1 transcriptional up-regulation in TTD is caused by an erroneous signaling mediated by retinoic acid receptors on the MMP-1 promoter and leads to hypersecretion of active MMP-1 enzyme and degradation of collagen type I in the ECM of cell/tissue systems and TTD patient skin. In agreement with the well-known role of ECM in eliciting signaling events controlling cell behavior and tissue homeostasis, ECM alterations in TTD were shown to impact on the migration and wound-healing properties of patient dermal fibroblasts. The presence of a specific inhibitor of MMP activity was sufficient to restore normal cell migration, thus providing a potential approach for therapeutic strategies. This study highlights the relevance of ECM anomalies in TTD pathogenesis and in the phenotypic differences between TTD and XP.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}