@article{%a1.%Yb_108,

title = {Ribosomal Dysfunction Is a Common Pathomechanism in Different Forms of Trichothiodystrophy},

author = {Zhu G and Khalid F and Zhang D and Cao Z and Maity P and Kestler HA and Orioli D and Scharffetter-Kochanek K and Iben S},

url = {https://www.mdpi.com/2073-4409/12/14/1877},

doi = {10.3390/cells12141877},

year  = {2023},

date = {2023-08-08},

journal = {Cells},

volume = {12},

issue = {14},

pages = {1877},

abstract = {Mutations in a broad variety of genes can provoke the severe childhood disorder trichothiodystrophy (TTD) that is classified as a DNA repair disease or a transcription syndrome of RNA polymerase II. In an attempt to identify the common underlying pathomechanism of TTD we performed a knockout/knockdown of the two unrelated TTD factors TTDN1 and RNF113A and investigated the consequences on ribosomal biogenesis and performance. Interestingly, interference with these TTD factors created a nearly uniform impact on RNA polymerase I transcription with downregulation of UBF, disturbed rRNA processing and reduction of the backbone of the small ribosomal subunit rRNA 18S. This was accompanied by a reduced quality of decoding in protein translation and the accumulation of misfolded and carbonylated proteins, indicating a loss of protein homeostasis (proteostasis). As the loss of proteostasis by the ribosome has been identified in the other forms of TTD, here we postulate that ribosomal dysfunction is a common underlying pathomechanism of TTD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Yb_71,

title = {TFIIH mutations can impact on translational fidelity of the ribosome},

author = {Khalid F and Phan T and Qiang M and Maity P and Lasser T and Wiese S and Penzo M and Alupei M and Orioli D and Scharffetter-Kochanek K and Iben S},

url = {https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac268/6779975?login=false},

doi = {10.1093/hmg/ddac268},

year  = {2023},

date = {2023-03-22},

journal = {Human molecular genetics},

volume = {32},

issue = {7},

pages = {1102-1113},

abstract = {TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I. Mutations in TFIIH cause the cancer prone DNA-repair disorder xeroderma pigmentosum (XP) and the developmental and premature aging disorders trichothiodystrophy (TTD) and Cockayne syndrome (CS). 50% of TTD cases are caused by TFIIH mutations. Using TFIIH mutant patient cells from TTD and XP subjects we can show that the stress-sensitivity of the proteome is reduced in TTD, but not in XP. Using three different methods to investigate the accuracy of protein synthesis by the ribosome, we demonstrate that translational fidelity of the ribosomes of TTD, but not XP cells, is decreased. The process of ribosomal synthesis and maturation is affected in TTD cells and can lead to instable ribosomes. Isolated ribosomes from TTD patients show an elevated error rate when challenged with oxidized mRNA, explaining the oxidative hypersensitivity of TTD cells. Treatment of TTD cells with N-acetyl cysteine normalized the increased translational error-rate and restored translational fidelity. Here we describe a pathomechanism that might be relevant for our understanding of impaired development and aging-associated neurodegeneration.},

keywords = {},

pubstate = {published},

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:%Y__512,

title = {Expansion of the clinical and molecular spectrum of an XPD-related disorder linked to biallelic mutations in ERCC2 gene},

author = {Agolini E and Botta E and Lodi M and Digilio MC and Rinelli M and Bellacchio E and Alesi V and Nardo T and Zambruno G and Orioli D and Alessi I and Boccuto L and Rossi S and Carai A and Colafati GS and Cacchione A and Dallapiccola B and Novelli A and Mastronuzzi A.},

url = {https://onlinelibrary.wiley.com/doi/10.1111/cge.13957},

doi = {10.1111/cge.13957},

year  = {2021},

date = {2021-04-14},

journal = {Clinical genetics},

volume = {99},

number = {6},

pages = {842-848},

abstract = {Bi-allelic inactivation of XPD protein, a nucleotide excision repair (NER) signaling pathway component encoded by ERCC2 gene, has been associated with several defective DNA repair phenotypes, including xeroderma pigmentosum, photosensitive trichothiodystrophy, and cerebro-oculo-facio-skeletal syndrome. We report a pediatric patient harboring two compound heterozygous variants in ERCC2 gene, c.361-1G > A and c.2125A > C (p.Thr709Pro), affected by severe postnatal growth deficiency, microcephaly, facial dysmorphisms and pilocytic astrocytoma of the brainstem. Some of these features point to a DNA repair syndrome, and altogether delineate a phenotype differentiating from disorders known to be associated with ERCC2 mutations. The DNA repair efficiency following UV irradiation in the proband's skin fibroblasts was defective indicating that the new set of ERCC2 alleles impacts on NER efficiency. Sequencing analysis on tumor DNA did not reveal any somatic deleterious point variant in cancer-related genes, while SNP-array analysis disclosed a 2 Mb microduplication involving the 7q34 region, spanning from KIAA1549 to BRAF, and resulting in the KIAA1549:BRAF fusion protein, a marker of pilocytic astrocytoma. In conclusion, this report expands the clinical and mutational spectrum of ERCC2-related disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y,

title = {Protein instability associated with AARS1 and MARS1 mutations causes Trichothiodystrophy},

author = {Botta E and Theil AF and Raams A and Caligiuri G and Giachetti S and Bione S and Accadia M and Lombardi A and Smith DEC and Mendes MI and Swagemakers SMA and van der Spek PJ and Salomons GS and Hoeijmakers JHJ and Yesodharan D and Nampoothiri S and Ogi T and Lehmann AR and Orioli D and Vermeulen W},

url = {https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddab123/6256034},

doi = {10.1093/hmg/ddab123},

year  = {2021},

date = {2021-05-14},

urldate = {2021-05-14},

journal = {Human molecular genetics},

volume = {30},

number = {1711},

issue = {18},

pages = {1720},

abstract = {Trichothiodystrophy (TTD) is a rare hereditary neurodevelopmental disorder defined by sulphur-deficient brittle hair and nails and scaly skin, but with otherwise remarkably variable clinical features. The photosensitive TTD (PS-TTD) form exhibits, in addition, progressive neuropathy and other features of segmental accelerated aging and is associated with impaired genome maintenance and transcription. New factors involved in various steps of gene expression have been identified for the different non-photosensitive forms of TTD (NPS-TTD), which do not appear to show features of premature aging. Here we identify AARS1 and MARS1 variants as new gene defects that cause NPS-TTD. These variants result in instability of the respective gene products alanyl- and methionyl-tRNA synthetase. These findings extend our previous observations that TTD mutations affect the stability of the corresponding proteins and emphasise this phenomenon as a common feature of TTD. Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging, the first step in protein translation. The extension of reduced abundance of TTD factors to translation as well as transcription, redefines TTD as a syndrome in which proteins involved in gene expression are unstable.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Ybv,

title = {Reduced levels of prostaglandin I 2 synthase: a distinctive feature of the cancer-free trichothiodystrophy},

author = {Lombardi A and Arseni L and Carriero R and Compe E and Botta E and Ferri D and Uggè M and Biamonti G and Peverali FA and Bione S and Orioli D},

url = {https://www.pnas.org/content/118/26/e2024502118.long},

doi = {10.1073/pnas.2024502118},

year  = {2021},

date = {2021-08-25},

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

volume = {118},

number = {26},

abstract = {The cancer-free photosensitive trichothiodystrophy (PS-TTD) and the cancer-prone xeroderma pigmentosum (XP) are rare monogenic disorders that can arise from mutations in the same genes, namely ERCC2/XPD or ERCC3/XPB Both XPD and XPB proteins belong to the 10-subunit complex transcription factor IIH (TFIIH) that plays a key role in transcription and nucleotide excision repair, the DNA repair pathway devoted to the removal of ultraviolet-induced DNA lesions. Compelling evidence suggests that mutations affecting the DNA repair activity of TFIIH are responsible for the pathological features of XP, whereas those also impairing transcription give rise to TTD. By adopting a relatives-based whole transcriptome sequencing approach followed by specific gene expression profiling in primary fibroblasts from a large cohort of TTD or XP cases with mutations in ERCC2/XPD gene, we identify the expression alterations specific for TTD primary dermal fibroblasts. While most of these transcription deregulations do not impact on the protein level, very low amounts of prostaglandin I2 synthase (PTGIS) are found in TTD cells. PTGIS catalyzes the last step of prostaglandin I2 synthesis, a potent vasodilator and inhibitor of platelet aggregation. Its reduction characterizes all TTD cases so far investigated, both the PS-TTD with mutations in TFIIH coding genes as well as the nonphotosensitive (NPS)-TTD. A severe impairment of TFIIH and RNA polymerase II recruitment on the PTGIS promoter is found in TTD but not in XP cells. Thus, PTGIS represents a biomarker that combines all PS- and NPS-TTD cases and distinguishes them from XP.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_451,

title = {Heterogeneity and overlaps in nucleotide excision repair disorders.},

author = {Ferri D and Orioli D and Botta E},

url = {https://onlinelibrary.wiley.com/doi/full/10.1111/cge.13545},

doi = {10.1111/cge.13545},

year  = {2020},

date = {2020-01-01},

journal = {Clinical Genetics},

volume = {97},

number = {1},

pages = {12-24},

abstract = {Nucleotide excision repair (NER) is an essential DNA repair pathway devoted to the removal of bulky lesions such as photoproducts induced by the ultraviolet (UV) component of solar radiation. Deficiencies in NER typically result in a group of heterogeneous distinct disorders ranging from the mild UV sensitive syndrome to the cancer-prone xeroderma pigmentosum and the neurodevelopmental/progeroid conditions trichothiodystrophy, Cockayne syndrome and cerebro-oculo-facio-skeletal-syndrome. A complicated genetic scenario underlines these disorders with the same gene linked to different clinical entities as well as different genes associated with the same disease. Overlap syndromes with combined hallmark features of different NER disorders can occur and sporadic presentations showing extra features of the hematological disorder Fanconi Anemia or neurological manifestations mimicking Hungtinton disease-like syndromes have been described. Here, we discuss the multiple functions of the five major pleiotropic NER genes (ERCC3/XPB, ERCC2/XPD, ERCC5/XPG, ERCC1 and ERCC4/XPF) and their relevance in phenotypic complexity. We provide an update of mutational spectra and examine genotype-phenotype relationships. Finally, the molecular defects that could explain the puzzling overlap syndromes are discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%_49,

title = {Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype.},

author = {Theil AF and Botta E and Raams A and Smith DEC and Mendes MI and Caligiuri G and Giachetti S and Bione S and Carriero R and Liberi G and Zardoni L and Swagemakers SMA and Salomons GS and Sarasin A and Lehmann A and van der Spek PJ and Ogi T and Hoeijmakers JHJ and Vermeulen W and Orioli D},

url = {https://www.sciencedirect.com/science/article/abs/pii/S0002929719302423?via%3Dihub},

doi = {10.1016/j.ajhg.2019.06.017},

year  = {2019},

date = {2019-02-13},

journal = {American Journal of Human Genetics},

volume = {105},

number = {2},

pages = {434-440},

abstract = {Brittle and "tiger-tail" hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features including ichthyosis, intellectual disability, decreased fertility, and short stature. As a result of premature abrogation of terminal differentiation, the hair is brittle and fragile and contains reduced cysteine content. Hypersensitivity to UV light is found in about half of individuals with TTD; all of these individuals harbor bi-allelic mutations in components of the basal transcription factor TFIIH, and these mutations lead to impaired nucleotide excision repair and basal transcription. Different genes have been found to be associated with non-photosensitive TTD (NPS-TTD); these include MPLKIP (also called TTDN1), GTF2E2 (also called TFIIEβ), and RNF113A. However, a relatively large group of these individuals with NPS-TTD have remained genetically uncharacterized. Here we present the identification of an NPS-TTD-associated gene, threonyl-tRNA synthetase (TARS), found by next-generation sequencing of a group of uncharacterized individuals with NPS-TTD. One individual has compound heterozygous TARS variants, c.826A>G (p.Lys276Glu) and c.1912C>T (p.Arg638∗), whereas a second individual is homozygous for the TARS variant: c.680T>C (p.Leu227Pro). We showed that these variants have a profound effect on TARS protein stability and enzymatic function. Our results expand the spectrum of genes involved in TTD to include genes implicated in amino acid charging of tRNA, which is required for the last step in gene expression, namely protein translation. We previously proposed that some of the TTD-specific features derive from subtle transcription defects as a consequence of unstable transcription factors. We now extend the definition of TTD from a transcription syndrome to a "gene-expression" syndrome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%y,

title = {Cockayne Syndrome Type a (CSA) Protein Protects Primary Human Keratinocytes from Senescence.},

author = {Cordisco S and Tinaburri L and Teson M and Orioli D and Cardin R and Degan P and Stefanini M and Zambruno G and Guerra L and Dellambra E},

url = {https://www.sciencedirect.com/science/article/pii/S0022202X18323212?via%3Dihub},

doi = {10.1016/j.jid.2018.06.181},

year  = {2019},

date = {2019-02-13},

journal = {Journal of investigative dermatology},

volume = {139},

number = {1},

pages = {38-59},

abstract = {Defects in Cockayne syndrome type A (CSA), a gene involved in nucleotide excision repair, cause an autosomal recessive syndrome characterized by growth failure, progressive neurological dysfunction, premature aging, and skin photosensitivity and atrophy. Beyond its role in DNA repair, the CSA protein has additional functions in transcription and oxidative stress response, which are not yet fully elucidated. Here, we investigated the role of CSA protein in primary human keratinocyte senescence. Primary keratinocytes from three CS-A patients displayed premature aging features, namely premature clonal conversion, high steady-state levels of ROS and 8-OH-hydroxyguanine (8-OH-Gua) and senescence-associated secretory phenotype (SASP). Stable transduction of CS-A keratinocytes with the wild-type CSA gene restored the normal cellular sensitivity to UV irradiation and normal 8-OH-Gua levels. Gene correction was also characterized by proper restoration of keratinocyte clonogenic capacity and expression of clonal conversion key regulators (p16 and p63), decreased NF-kB activity and, in turn, the expression of its targets (NOX1 and MnSOD), and the secretion of SASP mediators. Overall, the CSA protein plays an important role in protecting cells from senescence by facilitating DNA damage processing, maintaining physiological redox status and keratinocyte clonogenic ability, and reducing the SASP-mediated inflammatory phenotype.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_167,

title = {Epigenetic Regulation of Skin Cells in Natural Aging and Premature Aging Diseases.},

author = {Orioli D and Dellambra E},

url = {https://www.mdpi.com/2073-4409/7/12/268},

doi = {10.3390/cells7120268},

year  = {2018},

date = {2018-12-12},

journal = {Cells},

volume = {7},

number = {12},

pages = {268},

abstract = {Skin undergoes continuous renewal throughout an individual's lifetime relying on stem cell functionality. However, a decline of the skin regenerative potential occurs with age. The accumulation of senescent cells over time probably reduces tissue regeneration and contributes to skin aging. Keratinocytes and dermal fibroblasts undergo senescence in response to several intrinsic or extrinsic stresses, including telomere shortening, overproduction of reactive oxygen species, diet, and sunlight exposure. Epigenetic mechanisms directly regulate skin homeostasis and regeneration, but they also mark cell senescence and the natural and pathological aging processes. Progeroid syndromes represent a group of clinical and genetically heterogeneous pathologies characterized by the accelerated aging of various tissues and organs, including skin. Skin cells from progeroid patients display molecular hallmarks that mimic those associated with naturally occurring aging. Thus, investigations on progeroid syndromes strongly contribute to disclose the causal mechanisms that underlie the aging process. In the present review, we discuss the role of epigenetic pathways in skin cell regulation during physiologic and premature aging.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_109,

title = {From Structure to Phenotype: Impact of Collagen Alterations on Human Health.},

author = {Arseni L and Lombardi A and Orioli D},

url = {http://www.mdpi.com/1422-0067/19/5/1407},

doi = {10.3390/ijms19051407},

year  = {2018},

date = {2018-02-28},

journal = {International journal of molecular sciences},

volume = {19},

number = {5},

pages = {e1407},

abstract = {The extracellular matrix (ECM) is a highly dynamic and heterogeneous structure that plays multiple roles in living organisms. Its integrity and homeostasis are crucial for normal tissue development and organ physiology. Loss or alteration of ECM components turns towards a disease outcome. In this review, we provide a general overview of ECM components with a special focus on collagens, the most abundant and diverse ECM molecules. We discuss the different functions of the ECM including its impact on cell proliferation, migration and differentiation by highlighting the relevance of the bidirectional cross-talk between the matrix and surrounding cells. By systematically reviewing all the hereditary disorders associated to altered collagen structure or resulting in excessive collagen degradation, we point to the functional relevance of the collagen and therefore of the ECM elements for human health. Moreover, the large overlapping spectrum of clinical features of the collagen-related disorders makes in some cases the patient clinical diagnosis very difficult. A better understanding of ECM complexity and molecular mechanisms regulating the expression and functions of the various ECM elements will be fundamental to fully recognize the different clinical entities.},

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:%Y_173,

title = {Phenotypic variability in xeroderma pigmentosum group G: An uncommon case with severe prenatal-onset Cockayne syndrome features.},

author = {Ricotti R and Nardo T and Striano P and Stefanini M and Orioli D and Botta E},

url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/cge.13364},

doi = {10.1111/cge.13364.},

year  = {2018},

date = {2018-10-25},

journal = {Clinical Genetics},

volume = {94},

number = {3-4},

pages = {386-388},

abstract = {not available LETTER TO EDITOR},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_203,

title = {Digital PCR identifies changes in CDH1 (E-cadherin) transcription pattern in intestinal-type gastric cancer.},

author = {{Abou Khouzam R} and Molinari C and Salvi S and Marabelli M and Molinaro V and Orioli D and Saragoni L and Morgagni P and Calistri D and Ranzani GN},

url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=13401&pubmed-linkout=1},

doi = {10.18632/oncotarget.13401},

year  = {2017},

date = {2017-02-16},

journal = {Oncotarget},

volume = {8},

number = {12},

pages = {18811-18820},

abstract = {E-cadherin is a cell-cell adhesion protein encoded by CDH1 tumor-suppressor gene. CDH1 inactivating mutations, leading to loss of protein expression, are common in gastric cancer of the diffuse histotype, while alternative mechanisms modulating E-cadherin expression characterize the more common intestinal histotype. These mechanisms are still poorly understood. CDH1 intron 2 has recently emerged as a cis-modulator of E-cadherin expression, encoding non-canonical transcripts. One in particular, CDH1a, proved to be expressed in gastric cancer cell lines, while being absent in the normal stomach. For the first time, we evaluated by digital PCR the expression of CDH1 and CDH1a transcripts in cancer and normal tissue samples from 32 patients with intestinal-type gastric cancer. We found a significant decrease in CDH1 expression in tumors compared to normal counterparts (P = 0.001), which was especially evident in 76% of cases. CDH1a was detected at extremely low levels in 47% of tumors, but not in normal mucosa. A trend was observed of having less CDH1 in tumors expressing CDH1atranscript. The majority of tumors with both a decrease in CDH1 and presence of CDH1a also showed a decrease in miR-101 expression levels. On the whole, the decrease of CDH1 transcript, corresponding to the canonical protein, and the presence of CDH1a, corresponding to an alternative isoform, are likely to perturb E-cadherin-mediated signaling and cell-cell adhesion, thus contributing to intestinal-type gastric carcinogenesis.},

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_419,

title = {Studies on the ATP Binding Site of Fyn Kinase for the Identification of New Inhibitors and Their Evaluation as Potential Agents against Tauopathies and Tumors.},

author = {Tintori C and La Sala G and Vignaroli G and Botta L and Fallacara AL and Falchi F and Radi M and Zamperini C and Dreassi E and Dello Iacono L and Orioli D and Biamonti G and Garbelli M and Lossani A and Gasparrini F and Tuccinardi T and Laurenzana I and Angelucci A and Maga G and Schenone S and Brullo C and Musumeci F and Desogus A and Crespan E and Botta M},

url = {https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00140},

doi = {10.1021/acs.jmedchem.5b00140},

year  = {2015},

date = {2015-06-11},

journal = {Journal of Medicinal Chemistry},

volume = {58},

number = {11},

pages = {4590-4609},

abstract = {Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies, such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with K(i) of about 2 μM, while derivative 4a, derived from our internal library, showed a K(i) of 0.9 μM. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 4d having K(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines.},

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}

}