title: XPD mutations in trichothiodystrophy hamper collagen VI expression and reveal a role of TFIIH in transcription derepression.
abstract: Mutations in the XPD subunit of the transcription/DNA repair factor (TFIIH) give rise to trichothiodystrophy (TTD), a rare hereditary multisystem disorder with skin abnormalities. Here, we show that TTD primary dermal fibroblasts contain low amounts of collagen type VI alpha1 subunit (COL6A1), a fundamental component of soft connective tissues. We demonstrate that COL6A1 expression is downregulated by the sterol regulatory element-binding protein-1 (SREBP-1) whose removal from the promoter is a key step in COL6A1 transcription upregulation in response to cell confluence. We provide evidence for TFIIH being involved in transcription derepression, thus highlighting a new function of TFIIH in gene expression regulation. The lack of COL6A1 upregulation in TTD is caused by the inability of the mutated TFIIH complexes to remove SREBP-1 from COL6A1 promoter and to sustain the subsequent high rate of COL6A1 transcription. This defect might account for the pathologic features that TTD shares with hereditary disorders because of mutations in COL6A genes.
authors.affiliation: Istituto di Genetica Molecolare CNR, Pavia 27100, Italy. orioli@igm.cnr.it
authors.forename: Donata
authors.initials: D
authors.lastname: Orioli
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Compe
authors.forename: Tiziana
authors.initials: T
authors.lastname: Nardo
authors.forename: Manuela
authors.initials: M
authors.lastname: Mura
authors.forename: Christophe
authors.initials: C
authors.lastname: Giraudon
authors.forename: Elena
authors.initials: E
authors.lastname: Botta
authors.forename: Laura
authors.initials: L
authors.lastname: Arrigoni
authors.forename: Fiorenzo A
authors.initials: FA
authors.lastname: Peverali
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: Miria
authors.initials: M
authors.lastname: Stefanini
mesh_terms: D024142:Collagen Type VI / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051758:Transcription Factor TFIIH / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D054463:Trichothiodystrophy Syndromes / Q000235:genetics* / Q000378:metabolism; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C553839:Col6a1 protein, human; D024142:Collagen Type VI; D051758:Transcription Factor TFIIH; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human