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Am J Hum Genet. 2015 Feb 5;96(2):194-207. doi: 10.1016/j.ajhg.2014.12.012. Epub 2015 Jan 22.

TFIIH subunit alterations causing xeroderma pigmentosum and trichothiodystrophy specifically disturb several steps during transcription.

Author information

1
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.
2
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.
3
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.

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.

PMID:
25620205
PMCID:
PMC4320266
DOI:
10.1016/j.ajhg.2014.12.012
[Indexed for MEDLINE]
Free PMC Article

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