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
  • 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.

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