Architecture of the Human and Yeast General Transcription and DNA Repair Factor TFIIH.
Architecture of the Human and Yeast General Transcription and DNA Repair Factor TFIIH.
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DOI：
10.1016/j.molcel.2015.07.016
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发表时间：
2015-09-03
期刊：
影响因子：
16
通讯作者：
Ranish J
中科院分区：
文献类型：
--
作者：
Luo J;Cimermancic P;Viswanath S;Ebmeier CC;Kim B;Dehecq M;Raman V;Greenberg CH;Pellarin R;Sali A;Taatjes DJ;Hahn S;Ranish J
TFIIH对于RNA聚合酶II转录和DNA修复都是必不可少的，并且TFIIH中的突变可导致人类疾病。在这里，我们确定了人类和酵母TFIIH的分子结构的综合方法，使用化学交联/质谱（CXMS）数据，生化分析，和以前发表的电子显微镜图。我们确定了四个新的保守的“拓扑区域”，作为TFIIH组装的枢纽和超过35个保守的拓扑功能内TFIIH，照亮了TFIIH组装和调节其活动所涉及的相互作用网络。我们发现，这些保守的区域之一，p62/Tfb 1锚区，直接与DNA解旋酶亚基XPD/Rad 3在天然TFIIH相互作用，是必需的TFIIH的完整性和功能。我们还揭示了着色性干皮病和木硫营养不良患者缺陷的结构基础，在p62锚区和XPD亚基之间的界面处发现突变。
TFIIH is essential for both RNA polymerase II transcription and DNA repair, and mutations in TFIIH can result in human disease. Here, we determine the molecular architecture of human and yeast TFIIH by an integrative approach using chemical crosslinking/mass spectrometry (CXMS) data, biochemical analyses, and previously published electron microscopy maps. We identified four new conserved “topological regions” that function as hubs for TFIIH assembly and more than 35 conserved topological features within TFIIH, illuminating a network of interactions involved in TFIIH assembly and regulation of its activities. We show that one of these conserved regions, the p62/Tfb1 Anchor region, directly interacts with the DNA helicase subunit XPD/Rad3 in native TFIIH and is required for the integrity and function of TFIIH. We also reveal the structural basis for defects in patients with Xeroderma pigmentosum and Trichothiodystrophy, with mutations found at the interface between the p62 Anchor region and the XPD subunit.