Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH
Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH
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DOI：
10.1038/nn1990
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发表时间：
2007-11-01
影响因子：
25
通讯作者：
Egly, Jean-Marc
中科院分区：
文献类型：
--
作者：
Compe, Emmanuel;Malerba, Monica;Egly, Jean-Marc
DNA修复/转录因子TFIIH的XPD亚单位的突变会导致罕见的遗传性疾病毛发硫代营养不良(TTD)。虽然这种综合征最初与DNA修复缺陷有关，但TTD患者会出现神经系统特征，如小头畸形和髓鞘减少，这可能与转录缺陷有关。在这里，我们展示了TTD小鼠的XPD突变导致了大脑中甲状腺激素靶基因的空间和选择性的解除调控。对小鼠脑组织进行的分子分析表明，TFIIH是甲状腺激素受体(TR)稳定其DNA反应元件所必需的。因此，在患有TTD的个体中发现的TFIIH的限量有助于解除对TR反应基因的调控。TFIIH意想不到的稳定功能的发现加深了我们对TTD患者的发病机制和神经系统表现的理解。
Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH yield the rare genetic disorder trichothiodystrophy (TTD). Although this syndrome was initially associated with a DNA repair defect, individuals with TTD develop neurological features, such as microcephaly and hypomyelination that could be connected to transcriptional defects. Here we show that an XPD mutation in TTD mice results in a spatial and selective deregulation of thyroid hormone target genes in the brain. Molecular analyses performed on the mice brain tissue demonstrate that TFIIH is required for the stabilization of thyroid hormone receptors (TR) to their DNA-responsive elements. The limiting amounts of TFIIH found in individuals with TTD thus contribute to the deregulation of TR-responsive genes. The discovery of an unexpected stabilizing function for TFIIH deepens our understanding of the pathogenesis and neurological manifestations observed in TTD individuals.