Critical for transcription initiation and bulky lesion DNA repair, TFIIH provides an exemplary system to connect molecular mechanisms to biological outcomes due to its strong genetic links to different specific human diseases. Recent advances in structural and computational biology provide a unique opportunity to re-examine biologically relevant molecular structures and develop possible mechanistic insights for the large dynamic TFIIH complex. TFIIH presents many puzzles involving how its two SF2 helicase family enzymes, XPB and XPD, function in transcription initiation and repair: how do they initiate transcription, detect and verify DNA damage, select the damaged strand for incision, coordinate repair with transcription and cell cycle through Cdk-activating-kinase (CAK) signaling, and result in very different specific human diseases associated with cancer, aging, and development from single missense mutations? By joining analyses of breakthrough cryo-electron microscopy (cryo-EM) structures and advanced computation with data from biochemistry and human genetics, we develop unified concepts and molecular level understanding for TFIIH functions with a focus on structural mechanisms. We provocatively consider that TFIIH may have first evolved from evolutionary pressure for TCR to resolve arrested transcription blocks to DNA replication and later added its key roles in transcription initiation and global DNA repair. We anticipate that this level of mechanistic information will have significant impact on thinking about TFIIH, laying a robust foundation suitable to develop new paradigms for DNA transcription initiation and repair along with insights into disease prevention, susceptibility, diagnosis and interventions.

TFIIH 对转录起始和大面积损伤 DNA 修复至关重要，由于其与不同特定人类疾病的强大遗传联系，TFIIH 提供了一个示例系统，可将分子机制与生物学结果联系起来。结构和计算生物学的最新进展提供了一个独特的机会，可以重新检查生物相关的分子结构，并为大型动态 TFIIH 复合物开发可能的机械见解。TFIIH 提出了许多难题，涉及其两种 SF2 解旋酶家族酶 XPB 和 XPD 如何在转录起始和修复中发挥作用：它们如何启动转录、检测和验证 DNA 损伤、选择受损链进行切口、协调修复与转录和细胞周期通过 Cdk 激活激酶 (CAK) 信号，并从单个错义突变导致与癌症、衰老和发育相关的非常不同的特定人类疾病？通过将突破性低温电子显微镜 (cryo-EM) 结构的分析和高级计算与来自生物化学和人类遗传学的数据结合起来，我们为 TFIIH 功能开发了统一的概念和分子水平的理解，重点是结构机制。我们挑衅地认为 TFIIH 可能首先从 TCR 的进化压力演变而来，以解决被阻止的转录块到 DNA 复制，后来又增加了它在转录起始和全局 DNA 修复中的关键作用。我们预计这种级别的机械信息将对 TFIIH 的思考产生重大影响，