Molecular Model of Tfiih Recruitment to the Transcription-Coupled Repair Machinery

Authors

Tanmoy Paul
Chunli Yan
Jina Yu
Susan E Tsutakawa
John A Tainer
Dong Wang
Ivaylo Ivanov

Publication Date

3-8-2025

Journal

Nature Communications

Abstract

Transcription-coupled repair (TCR) is a vital nucleotide excision repair sub-pathway that removes DNA lesions from actively transcribed DNA strands. Binding of CSB to lesion-stalled RNA Polymerase II (Pol II) initiates TCR by triggering the recruitment of downstream repair factors. Yet it remains unknown how transcription factor IIH (TFIIH) is recruited to the intact TCR complex. Combining existing structural data with AlphaFold predictions, we build an integrative model of the initial TFIIH-bound TCR complex. We show how TFIIH can be first recruited in an open repair-inhibited conformation, which requires subsequent CAK module removal and conformational closure to process damaged DNA. In our model, CSB, CSA, UVSSA, elongation factor 1 (ELOF1), and specific Pol II and UVSSA-bound ubiquitin moieties come together to provide interaction interfaces needed for TFIIH recruitment. STK19 acts as a linchpin of the assembly, orienting the incoming TFIIH and bridging Pol II to core TCR factors and DNA. Molecular simulations of the TCR-associated CRL4

Keywords

Transcription Factor TFIIH, DNA Repair, Humans, RNA Polymerase II, DNA Helicases, DNA Repair Enzymes, Poly-ADP-Ribose Binding Proteins, Transcription, Genetic, Models, Molecular, DNA Damage, Protein Binding, DNA-Binding Proteins, DNA, Excision Repair, Carrier Proteins

DOI

10.1038/s41467-025-57593-0

PMID

40057514

PMCID

PMC11890784

PubMedCentral® Posted Date

3-8-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes