Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 4310 |
| Tidsskrift | Nature Communications |
| Vol/bind | 14 |
| Udgave nummer | 1 |
| Antal sider | 14 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We thank Ivan Ahel (University of Oxford) for the HPF1 and ARH3 knock-out cells and Thanos Halazonetis for the BIR reporter constructs. This research was funded in whole, or in part, by the Wellcome Trust (Grant 102348/Z/13/Z) and MRC (Grants MR/P028284/1; MR/P018963/1; MR/V00896X/1; MR/W017350/1). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. JL was supported by AstraZeneca. M.L.N. lab is supported by the Novo Nordisk Foundation (NNF14CC0001; NNF13OC0006477), Danish Council of Independent Research (4002-00051, 4183-00322 A, 8020-00220B; 0135-00096B) and The Danish Cancer Society (R146-A9159-16-S2). The proteomics technology was funded by the EU’s Horizon 2020 research and innovation programme (EPIC-XS-823839).
Funding Information:
We thank Ivan Ahel (University of Oxford) for the HPF1 and ARH3 knock-out cells and Thanos Halazonetis for the BIR reporter constructs. This research was funded in whole, or in part, by the Wellcome Trust (Grant 102348/Z/13/Z) and MRC (Grants MR/P028284/1; MR/P018963/1; MR/V00896X/1; MR/W017350/1). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. JL was supported by AstraZeneca. M.L.N. lab is supported by the Novo Nordisk Foundation (NNF14CC0001; NNF13OC0006477), Danish Council of Independent Research (4002-00051, 4183-00322 A, 8020-00220B; 0135-00096B) and The Danish Cancer Society (R146-A9159-16-S2). The proteomics technology was funded by the EU’s Horizon 2020 research and innovation programme (EPIC-XS-823839).
Publisher Copyright:
© 2023, The Author(s).
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