PARP1-DNA co-condensation drives DNA repair site assembly to prevent disjunction of broken DNA ends

DNA double-strand breaks (DSBs) are repaired at DSB sites. How DSB sites assemble and how broken DNA is prevented from separating is not understood. Here we uncover that the synapsis of broken DNA is mediated by the DSB sensor protein poly(ADP-ribose) (PAR) polymerase 1 (PARP1). Using bottom-up biochemistry, we reconstitute functional DSB sites and show that DSB sites form through co-condensation of PARP1 multimers with DNA. The co-condensates exert mechanical forces to keep DNA ends together and become enzymatically active for PAR synthesis. PARylation promotes release of PARP1 from DNA ends and the recruitment of effectors, such as Fused in Sarcoma, which stabilizes broken DNA ends against separation,…

• NS
  National Science Foundation

  Award: KP-06-N21-9
• EM
  European Molecular Biology Organization

  Award: ALTF 261-2020
• DF
  Deutsche Forschungsgemeinschaft

  Awards: EXC-2068– 390729961, 471025906
• VF
  Volkswagen Foundation
• SN
  Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

  Award: P2ZHP3_187653
• TU
  Technische Universität Dresden
• M
  Max-Planck-Gesellschaft

  Award: 96827
• SN
  Stavros Niarchos Foundation
• SS
  Sächsisches Staatsministerium für Wissenschaft und Kunst
• ER
  European Research Council
• ER
  European Regional Development Fund
• HE
  H2020 European Research Council

  Award: 725836