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Transcription-coupled DNA-protein crosslink repair by CSB and CRL4CSA-mediated degradation. 2024
Marjolein van Sluis, and
Qing Yu, and
Melanie van der Woude, and
Camila Gonzalo-Hansen, and
Shannon C Dealy, and
Roel C Janssens, and
Hedda B Somsen, and
Anisha R Ramadhin, and
Dick H W Dekkers, and
Hannah Lena Wienecke, and
Joris J P G Demmers, and
Anja Raams, and
Carlota Davó-Martínez, and
Diana A Llerena Schiffmacher, and
Marvin van Toorn, and
David Häckes, and
Karen L Thijssen, and
Di Zhou, and
Judith G Lammers, and
Alex Pines, and
Wim Vermeulen, and
Joris Pothof, and
Jeroen A A Demmers, and
Debbie L C van den Berg, and
Hannes Lans, and
Jurgen A Marteijn
Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
DNA-protein crosslinks (DPCs) arise from enzymatic intermediates, metabolism or chemicals like chemotherapeutics. DPCs are highly cytotoxic as they impede DNA-based processes such as replication, which is counteracted through proteolysis-mediated DPC removal by spartan (SPRTN) or the proteasome. However, whether DPCs affect transcription and how transcription-blocking DPCs are repaired remains largely unknown. Here we show that DPCs severely impede RNA polymerase II-mediated transcription and are preferentially repaired in active genes by transcription-coupled DPC (TC-DPC) repair. TC-DPC repair is initiated by recruiting the transcription-coupled nucleotide excision repair (TC-NER) factors CSB and CSA to DPC-stalled RNA polymerase II. CSA and CSB are indispensable for TC-DPC repair; however, the downstream TC-NER factors UVSSA and XPA are not, a result indicative of a non-canonical TC-NER mechanism. TC-DPC repair functions independently of SPRTN but is mediated by the ubiquitin ligase CRL4CSA and the proteasome. Thus, DPCs in genes are preferentially repaired in a transcription-coupled manner to facilitate unperturbed transcription.
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