Dynamic conformational switching underlies TFIIH function in transcription and DNA repair and impacts genetic diseases

Jina Yu, Chunli Yan, Thomas Dodd, Chi-Lin Tsai, John A. Tainer, Susan E. Tsutakawa and Ivaylo Ivanov ()
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Jina Yu: Georgia State University
Chunli Yan: Georgia State University
Thomas Dodd: Georgia State University
Chi-Lin Tsai: The University of Texas MD Anderson Cancer Center
John A. Tainer: The University of Texas MD Anderson Cancer Center
Susan E. Tsutakawa: Lawrence Berkeley National Laboratory
Ivaylo Ivanov: Georgia State University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Transcription factor IIH (TFIIH) is a protein assembly essential for transcription initiation and nucleotide excision repair (NER). Yet, understanding of the conformational switching underpinning these diverse TFIIH functions remains fragmentary. TFIIH mechanisms critically depend on two translocase subunits, XPB and XPD. To unravel their functions and regulation, we build cryo-EM based TFIIH models in transcription- and NER-competent states. Using simulations and graph-theoretical analysis methods, we reveal TFIIH’s global motions, define TFIIH partitioning into dynamic communities and show how TFIIH reshapes itself and self-regulates depending on functional context. Our study uncovers an internal regulatory mechanism that switches XPB and XPD activities making them mutually exclusive between NER and transcription initiation. By sequentially coordinating the XPB and XPD DNA-unwinding activities, the switch ensures precise DNA incision in NER. Mapping TFIIH disease mutations onto network models reveals clustering into distinct mechanistic classes, affecting translocase functions, protein interactions and interface dynamics.

Date: 2023
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DOI: 10.1038/s41467-023-38416-6

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