PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress

Daniela Muoio, Natalie Laspata, Rachel L. Dannenberg, Caroline Curry, Simone Darkoa-Larbi, Mark Hedglin, Shikhar Uttam and Elise Fouquerel ()
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Daniela Muoio: Department of Pharmacology and Chemical Biology
Natalie Laspata: Department of Pharmacology and Chemical Biology
Rachel L. Dannenberg: University park
Caroline Curry: Thomas Jefferson University
Simone Darkoa-Larbi: Thomas Jefferson University
Mark Hedglin: University park
Shikhar Uttam: University of Pittsburgh
Elise Fouquerel: Department of Pharmacology and Chemical Biology

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract PARP2 is a DNA-dependent ADP-ribosyl transferase (ARTs) enzyme with Poly(ADP-ribosyl)ation activity that is triggered by DNA breaks. It plays a role in the Base Excision Repair pathway, where it has overlapping functions with PARP1. However, additional roles for PARP2 have emerged in the response of cells to replication stress. In this study, we demonstrate that PARP2 promotes replication stress-induced telomere fragility and prevents telomere loss following chronic induction of oxidative DNA lesions and BLM helicase depletion. Telomere fragility results from the activity of the break-induced replication pathway (BIR). During this process, PARP2 promotes DNA end resection, strand invasion and BIR-dependent mitotic DNA synthesis by orchestrating POLD3 recruitment and activity. Our study has identified a role for PARP2 in the response to replication stress. This finding may lead to the development of therapeutic approaches that target DNA-dependent ART enzymes, particularly in cancer cells with high levels of replication stress.

Date: 2024
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DOI: 10.1038/s41467-024-47222-7

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