XPD mutations in trichothiodystrophy hamper collagen VI expression and reveal a role of TFIIH in transcription derepression

Donata Orioli, Emmanuel Compe, Tiziana Nardo, Manuela Mura, Christophe Giraudon, Elena Botta, Laura Arrigoni, Fiorenzo A. Peverali, Jean Marc Egly, Miria Stefanini

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the XPD subunit of the transcription/DNA repair factor (TFIIH) give rise to trichothiodyst ophy (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.

Original languageEnglish
Pages (from-to)1061-1073
Number of pages13
JournalHuman Molecular Genetics
Volume22
Issue number6
DOIs
Publication statusPublished - Mar 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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