Dynamic Conformational Switching Underlies Tfiih Function in Transcription and DNA Repair and Impacts Genetic Diseases

Authors

Jina Yu
Chunli Yan
Thomas Dodd
Chi-Lin Tsai
John A Tainer
Susan E Tsutakawa
Ivaylo Ivanov

Publication Date

5-13-2023

Journal

Nature Communications

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.

Keywords

Transcription Factor TFIIH, DNA Repair, DNA Helicases, Molecular Conformation, DNA, Transcription, Genetic

DOI

10.1038/s41467-023-38416-6

PMID

37179334

PMCID

PMC10183003

PubMedCentral® Posted Date

5-13-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes