PARP1 revisited - integrating DNA repair, replication and therapeutics.

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is a central regulator of genome integrity and a major therapeutic target in cancer. It is a versatile reader of DNA and chromatin architecture, engaging canonical DNA strand breaks as well as replication-associated and non-canonical DNA structures, including unligated Okazaki fragments, stalled or reversed replication forks, G-quadruplexes, and R-loops. However, how PARP1 recognizes these diverse substrates, and whether they elicit distinct ADP-ribosylation outputs, remains unclear. In this Review, we propose that PARP1 does not respond to DNA damage as a uniform sensor but instead interprets lesion geometry, DNA topology and chromatin context, resulting in dynamic control of chromatin accessibility, repair-factor recruitment, replication fork remodelling, transcription-replication conflicts and PARP1 turnover at DNA lesions. This evolving understanding has important therapeutic implications. PARP inhibitor efficacy, toxicity and resistance are not determined solely by catalytic inhibition or by BRCA1 and BRCA2 status but reflect the combined effects of PARP1 retention, replication stress, repair-pathway choice, chromatin remodelling and tumour context.

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