title: TFIIH subunit alterations causing xeroderma pigmentosum and trichothiodystrophy specifically disturb several steps during transcription.
abstract: Mutations in genes encoding the ERCC3 (XPB), ERCC2 (XPD), and GTF2H5 (p8 or TTD-A) subunits of the transcription and DNA-repair factor TFIIH lead to three autosomal-recessive disorders: xeroderma pigmentosum (XP), XP associated with Cockayne syndrome (XP/CS), and trichothiodystrophy (TTD). Although these diseases were originally associated with defects in DNA repair, transcription deficiencies might be also implicated. By using retinoic acid receptor beta isoform 2 (RARB2) as a model in several cells bearing mutations in genes encoding TFIIH subunits, we observed that (1) the recruitment of the TFIIH complex was altered at the activated RARB2 promoter, (2) TFIIH participated in the recruitment of nucleotide excision repair (NER) factors during transcription in a manner different from that observed during NER, and (3) the different TFIIH variants disturbed transcription by having distinct consequences on post-translational modifications of histones, DNA-break induction, DNA demethylation, and gene-loop formation. The transition from heterochromatin to euchromatin was disrupted depending on the variant, illustrating the fact that TFIIH, by contributing to NER factor recruitment, orchestrates chromatin remodeling. The subtle transcriptional differences found between various TFIIH variants thus participate in the phenotypic variability observed among XP, XP/CS, and TTD individuals.
authors.affiliation: Genome Expression and Repair Team, Labellisée Ligue contre le Cancer 2014, Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, Université de Strasbourg, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France.
authors.forename: Amita
authors.initials: A
authors.lastname: Singh
authors.affiliation: Genome Expression and Repair Team, Labellisée Ligue contre le Cancer 2014, Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, Université de Strasbourg, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Compe
authors.affiliation: Genome Expression and Repair Team, Labellisée Ligue contre le Cancer 2014, Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, Université de Strasbourg, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France. Electronic address: nlemay@igbmc.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Le May
authors.affiliation: Genome Expression and Repair Team, Labellisée Ligue contre le Cancer 2014, Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, Université de Strasbourg, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France. Electronic address: egly@igbmc.fr.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
mesh_terms: D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051758:Transcription Factor TFIIH / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*; D054463:Trichothiodystrophy Syndromes / Q000235:genetics*; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C512380:GTF2H5 protein, human; D046912:Multiprotein Complexes; C533416:RARB2 protein, human; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; C072022:XPBC-ERCC-3 protein; D051758:Transcription Factor TFIIH; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human