A Population-Specific PARP1 Gene Variation Modulates PARP Trapping.

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</

SUBMITTER: Cai J 

PROVIDER: S-EPMC12642684 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature