A Population-Specific PARP1 Gene Variation Modulates PARP Trapping

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ABSTRACT Poly-(ADP-ribose) polymerase inhibitors (PARPi) block NAD + -binding pocket of PARP1, inhibiting PAR synthesis. However, they differ in their ability to retain PARP1 on damaged DNA to induce synthetic lethality in homologous recombination-deficient (HRD) cancer. Allosteric enzymatic activation requires destabilization of the helical domain (HD) of PARP1 and is indispensable for activation and chromatin retention induced by distinct PARPi. Here we report that the effect of the clinical PARPi talazoparib is robustly impacted by a common human polymorphism within the HD. PARP1 V762 greatly enhanced talazoparib-driven allosteric retention on chromatin, prolonged XRCC1 recruitment, and enhanced cell killing. Talazoparib switches from Type-II PARPi behavior in PARP1 A762 to allosteric, pro-retention Type-I behavior for PARP1 V762 . Thus, both PARPi efficacy and dose-limiting tolerability depends on PARP1 allele, motivating variant-guided cancer therapies. TEASER One of the four FDA-approved PARPi drugs, talazoparib, is modulated by a PARP1 SNP that is widespread in the population.

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