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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.

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