Molecular model of TFIIH recruitment to the transcription-coupled repair machinery
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 r...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57593-0 |
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| author | Tanmoy Paul Chunli Yan Jina Yu Susan E. Tsutakawa John A. Tainer Dong Wang Ivaylo Ivanov |
| author_facet | Tanmoy Paul Chunli Yan Jina Yu Susan E. Tsutakawa John A. Tainer Dong Wang Ivaylo Ivanov |
| author_sort | Tanmoy Paul |
| collection | DOAJ |
| description | 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 CRL4CSA ubiquitin ligase complex unveil the interplay of segmental DDB1 flexibility, continuous Cullin4A flexibility, and the key role of ELOF1 for Pol II ubiquitination that enables TCR. Collectively, these findings elucidate the coordinated assembly of repair proteins in early TCR. |
| format | Article |
| id | doaj-art-50a36252ed9d45da9ddc11cbefcbf411 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-50a36252ed9d45da9ddc11cbefcbf4112025-08-20T01:57:45ZengNature PortfolioNature Communications2041-17232025-03-0116111710.1038/s41467-025-57593-0Molecular model of TFIIH recruitment to the transcription-coupled repair machineryTanmoy Paul0Chunli Yan1Jina Yu2Susan E. Tsutakawa3John A. Tainer4Dong Wang5Ivaylo Ivanov6Department of Chemistry, Georgia State UniversityDepartment of Chemistry, Georgia State UniversityDepartment of Chemistry, Georgia State UniversityMolecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National LaboratoryMolecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National LaboratoryDivision of Pharmaceutical Sciences, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of CaliforniaDepartment of Chemistry, Georgia State UniversityAbstract 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 CRL4CSA ubiquitin ligase complex unveil the interplay of segmental DDB1 flexibility, continuous Cullin4A flexibility, and the key role of ELOF1 for Pol II ubiquitination that enables TCR. Collectively, these findings elucidate the coordinated assembly of repair proteins in early TCR.https://doi.org/10.1038/s41467-025-57593-0 |
| spellingShingle | Tanmoy Paul Chunli Yan Jina Yu Susan E. Tsutakawa John A. Tainer Dong Wang Ivaylo Ivanov Molecular model of TFIIH recruitment to the transcription-coupled repair machinery Nature Communications |
| title | Molecular model of TFIIH recruitment to the transcription-coupled repair machinery |
| title_full | Molecular model of TFIIH recruitment to the transcription-coupled repair machinery |
| title_fullStr | Molecular model of TFIIH recruitment to the transcription-coupled repair machinery |
| title_full_unstemmed | Molecular model of TFIIH recruitment to the transcription-coupled repair machinery |
| title_short | Molecular model of TFIIH recruitment to the transcription-coupled repair machinery |
| title_sort | molecular model of tfiih recruitment to the transcription coupled repair machinery |
| url | https://doi.org/10.1038/s41467-025-57593-0 |
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