title: Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts.
abstract: Trichothiodystrophy (TTD) is a rare autosomal premature-ageing and neuroectodermal disease. The photohypersensitive form of TTD is caused by inherited mutations in three of the 10 subunits of the basal transcription factor TFIIH. TFIIH is an essential transcription initiation factor that is also pivotal for nucleotide excision repair (NER). Photosensitive TTD is explained by deficient NER, dedicated to removing UV-induced DNA lesions. TTD group A (TTD-A) patients carry mutations in the smallest TFIIH subunit, TTDA, which is an 8-kDa protein that dynamically interacts with TFIIH. TTD-A patients display a relatively mild TTD phenotype, and TTD-A primary fibroblasts exhibit moderate UV sensitivity despite a rather low level of UV-induced unscheduled DNA synthesis (UDS). To investigate the rationale of this seeming discrepancy, we studied the repair kinetics and the binding kinetics of TFIIH downstream NER factors to damaged sites in TTD-A cells. Our results show that TTD-A cells do repair UV lesions, although with reduced efficiency, and that the binding of downstream NER factors on damaged DNA is not completely abolished but only retarded. We conclude that in TTD-A cells repair is not fully compromised but only delayed, and we present a model that explains the relatively mild photosensitive phenotype observed in TTD-A patients.
authors: Department of Genetics, Erasmus MC, Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors: Arjan F
authors: AF
authors: Theil
authors: Julie
authors: J
authors: Nonnekens
authors: Nils
authors: N
authors: Wijgers
authors: Wim
authors: W
authors: Vermeulen
authors: Giuseppina
authors: G
authors: Giglia-Mari
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D011740:Pyrimidine Dimers / Q000378:metabolism; D013997:Time Factors; D051758:Transcription Factor TFIIH / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D054463:Trichothiodystrophy Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C512380:GTF2H5 protein, human; D011740:Pyrimidine Dimers; D014157:Transcription Factors; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C058406:pyrimidine-pyrimidone dimer; D051758:Transcription Factor TFIIH; D004247:DNA; C071447:ERCC1 protein, human; D004720:Endonucleases