1. Academic Validation
  2. Transcription-coupled DNA-protein crosslink repair by CSB and CRL4CSA-mediated degradation

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

  • Nat Cell Biol. 2024 Apr 10. doi: 10.1038/s41556-024-01394-y.
Marjolein van Sluis 1 Qing Yu # 1 Melanie van der Woude # 1 Camila Gonzalo-Hansen 1 Shannon C Dealy 1 Roel C Janssens 1 Hedda B Somsen 2 Anisha R Ramadhin 1 Dick H W Dekkers 3 Hannah Lena Wienecke 1 Joris J P G Demmers 1 Anja Raams 1 Carlota Davó-Martínez 1 Diana A Llerena Schiffmacher 1 Marvin van Toorn 1 David Häckes 1 Karen L Thijssen 1 Di Zhou 1 Judith G Lammers 1 Alex Pines 1 Wim Vermeulen 1 Joris Pothof 1 Jeroen A A Demmers 3 Debbie L C van den Berg 2 Hannes Lans 1 Jurgen A Marteijn 4
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 2 Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 3 Proteomics Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 4 Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands. j.marteijn@erasmusmc.nl.
  • # Contributed equally.
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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