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  • Transcription-coupled DNA-protein crosslink repair by CSB and CRL4CSA-mediated degradation.

Transcription-coupled DNA-protein crosslink repair by CSB and CRL4CSA-mediated degradation.

Nature cell biology (2024-04-11)
Marjolein van Sluis, Qing Yu, Melanie van der Woude, Camila Gonzalo-Hansen, Shannon C Dealy, Roel C Janssens, Hedda B Somsen, Anisha R Ramadhin, Dick H W Dekkers, Hannah Lena Wienecke, Joris J P G Demmers, Anja Raams, Carlota Davó-Martínez, Diana A Llerena Schiffmacher, Marvin van Toorn, David Häckes, Karen L Thijssen, Di Zhou, Judith G Lammers, Alex Pines, Wim Vermeulen, Joris Pothof, Jeroen A A Demmers, Debbie L C van den Berg, Hannes Lans, Jurgen A Marteijn
ABSTRACT

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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