Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair. The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation. Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology. Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 Å resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Additionally, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity.

中文翻译：

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人转录因子IIH的冷冻电镜结构

人类转录因子 IIH (TFIIH) 是 RNA 聚合酶 II 启动真核基因转录所需的一般转录机制的一部分。TFIIH 由十个亚基组成，加起来分子量约为 500 kDa，对于核苷酸切除修复也是必不可少的。由 XPB、XPD、p62、p52、p44、p34 和 p8 形成的七亚基 TFIIH 核心复合物能够进行 DNA 修复，而 CDK 激活激酶亚复合物，包括 CDK7 的激酶活性以及细胞周期蛋白 H和 MAT1 亚基，另外还需要转录起始。TFIIH 亚基 XPB、XPD 和 p8 的突变导致遗传性疾病色素性干皮病、Cockayne 综合征和毛发硫营养不良的严重过早衰老和癌症倾向，突出了 TFIIH 对细胞生理学的重要性。在这里，我们以 4.4 Å 的分辨率展示了人类 TFIIH 的低温电子显微镜结构。该结构揭示了 TFIIH 核心复合物的分子结构、其组成 XPB 和 XPD ATP 酶的详细结构，以及 TFIIH 的核心和激酶亚复合物是如何连接的。此外，我们的结构提供了对 TFIIH 构象动力学及其活性调节的洞察。