biostudies-literaturePaul TU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)NIEHS NIH HHSU.S. Department of Health & Human Services | NIH | National Cancer InstituteU.S. Department of Health & Human Services | NIH | National Institute of Environmental Health SciencesNational Science Foundation (NSF)NCI NIH HHSNIGMS NIH HHSNational Science Foundation2341https://www.ebi.ac.uk/biostudies/studies/S-EPMC11890784biostudies-literatureUnknown16(1)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 ubiquitinNature communicationsMolecular model of TFIIH recruitment to the transcription-coupled repair machinery.PMC11890784MCB 2027902R35GM139382R35 GM139382R01 ES032786P01 CA092584R35 CA220430R01 GM102362Tainer JAWang DIvanov IYan CTsutakawa SEYu JPaul TfalseMolecular model of TFIIH recruitment to the transcription-coupled repair machinery.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 ubiquitin2025-01-01T00:00:00Z2025 Mar2026-06-01T20:12:06.811Z2025-04-06T08:34:39.034ZS-EPMC118907844005751410.1038/s41467-025-57593-0