Visualization of stepwise derepression of TFIIH in global genome nucleotide excision repair

Nucleotide excision repair (NER) is a crucial DNA repair pathway that is orchestrated by transcription factor IIH (TFIIH) in eukaryotic cells. TFIIH is a multifunctional complex that contains two DNA helicase/DNA translocase subunits and a kinase module, different subsets of which act in NER, transcription initiation, and cell cycle control. To ensure fidelity despite multifunctionality, the DNA helicase activity of TFIIH is autoinhibited in its free form or when the factor engages in transcription initiation. While the release of the kinase module has been identified as a key step in TFIIH activation, the molecular mechanisms controlling this step and concomitant structural changes in TFIIH are incompletely understood. Here, we determine high-resolution structures of three NER intermediates that visualize how TFIIH arrives at sites of DNA damage in an autoinhibited state and how autoinhibition is released via previously undescribed intermediates. These findings contribute to a mechanistic understanding of human DNA repair.