Architecture of the Human and Yeast General Transcription and DNA Repair Factor TFIIH

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. [Display omitted] •Architecture of human and yeast TFIIH revealed by an integrative approach•Identified four topological regions that function as hubs for TFIIH assembly•The p62/Tfb1 Anchor region is required for the integrity and function of TFIIH•Structural basis for defects in patients with XP and TTD revealed Luo et al. used an integrative approach to define the molecular architecture of both human and yeast general transcription and DNA repair factor TFIIH. They identified several conserved topological features that can explain how TFIIH enzymatic activities are regulated.