
Faculty, Staff and Student Publications
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
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons