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

Frederick Richards, Marta J. Llorca-Cardenosa, Jamie Langton, Sara C. Buch-Larsen, Noor F. Shamkhi, Abhishek Bharadwaj Sharma, Michael L. Nielsen and Nicholas D. Lakin ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40071-w

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