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Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3

Author

Listed:
  • Frederick Richards

    (University of Oxford)

  • Marta J. Llorca-Cardenosa

    (University of Oxford)

  • Jamie Langton

    (University of Oxford)

  • Sara C. Buch-Larsen

    (University of Copenhagen)

  • Noor F. Shamkhi

    (University of Oxford)

  • Abhishek Bharadwaj Sharma

    (University of Oxford)

  • Michael L. Nielsen

    (University of Copenhagen)

  • Nicholas D. Lakin

    (University of Oxford)

Abstract

Although Poly(ADP-ribose)-polymerases (PARPs) are key regulators of genome stability, how site-specific ADP-ribosylation regulates DNA repair is unclear. Here, we describe a novel role for PARP1 and PARP2 in regulating Rad52-dependent replication fork repair to maintain cell viability when homologous recombination is dysfunctional, suppress replication-associated DNA damage, and maintain genome stability. Mechanistically, Mre11 and ATM are required for induction of PARP activity in response to replication stress that in turn promotes break-induced replication (BIR) through assembly of Rad52 at stalled/damaged replication forks. Further, by mapping ADP-ribosylation sites induced upon replication stress, we identify that PolD3 is a target for PARP1/PARP2 and that its site-specific ADP-ribosylation is required for BIR activity, replication fork recovery and genome stability. Overall, these data identify a critical role for Mre11-dependent PARP activation and site-specific ADP-ribosylation in regulating BIR to maintain genome integrity during DNA synthesis.

Suggested Citation

  • Frederick Richards & Marta J. Llorca-Cardenosa & Jamie Langton & Sara C. Buch-Larsen & Noor F. Shamkhi & Abhishek Bharadwaj Sharma & Michael L. Nielsen & Nicholas D. Lakin, 2023. "Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40071-w
    DOI: 10.1038/s41467-023-40071-w
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    1. Edoardo José Longarini & Ivan Matić, 2024. "Preserving ester-linked modifications reveals glutamate and aspartate mono-ADP-ribosylation by PARP1 and its reversal by PARG," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Daniela Muoio & Natalie Laspata & Rachel L. Dannenberg & Caroline Curry & Simone Darkoa-Larbi & Mark Hedglin & Shikhar Uttam & Elise Fouquerel, 2024. "PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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