TY - JOUR
T1 - XPD mutations in trichothiodystrophy hamper collagen VI expression and reveal a role of TFIIH in transcription derepression
AU - Orioli, Donata
AU - Compe, Emmanuel
AU - Nardo, Tiziana
AU - Mura, Manuela
AU - Giraudon, Christophe
AU - Botta, Elena
AU - Arrigoni, Laura
AU - Peverali, Fiorenzo A.
AU - Egly, Jean Marc
AU - Stefanini, Miria
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/dds508
DO - 10.1093/hmg/dds508
M3 - Article
C2 - 23221806
AN - SCOPUS:84874520401
VL - 22
SP - 1061
EP - 1073
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 6
ER -