Istituto di Genetica Molecolare CNR, Pavia 27100, Italy.
Hum Mol Genet. 2013 Mar 15;22(6):1061-73. doi: 10.1093/hmg/dds508. Epub 2012 Dec 5.
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.
转录/DNA 修复因子（TFIIH）的 XPD 亚基突变导致毛发硫营养不良症（TTD），这是一种罕见的遗传性多系统疾病，伴有皮肤异常。在这里，我们表明 TTD 原发性真皮成纤维细胞中含有低量的胶原蛋白 VI 亚型α1 亚基（COL6A1），这是软结缔组织的基本成分。我们证明 COL6A1 的表达受固醇调节元件结合蛋白-1（SREBP-1）下调，其从启动子上的去除是 COL6A1 转录在细胞汇合时上调的关键步骤。我们提供了 TFIIH 参与转录去抑制的证据，从而突出了 TFIIH 在基因表达调控中的新功能。TTD 中 COL6A1 上调的缺失是由于突变的 TFIIH 复合物无法从 COL6A1 启动子上去除 SREBP-1，并且无法维持随后的 COL6A1 转录的高速率。这种缺陷可能解释了 TTD 与由于 COL6A 基因突变引起的遗传性疾病共享的病理特征。
