2. Academic Validation
  3. 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. [email protected].
  • # Contributed equally.
PMID: 38600236 DOI: 10.1038/s41556-024-01394-y
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.

Figures
Products