Slow Dissociation from the PARP1-HPF1 Complex Drives Inhibitor Potency.

ABSTRACT: PARP1, upon binding to damaged DNA, is activated to perform poly ADP-ribosylation (PARylation) on itself and other proteins, which leads to relaxation of chromatin and recruitment of DNA repair factors. HPF1 was recently discovered as a protein cofactor of PARP1 that directs preferential PARylation of histones over other targets by contributing to and altering the PARP1 active site. Inhibitors of PARP1 (PARPi) are used in the treatment of BRCA-/- cancers, but the basis for their potency in cells, especially in the context of HPF1, is not fully understood. Here, we demonstrate the simple one-step association for eight different PARPi to PARP1 with measured rates of association (k_on) of 0.8-6 μM^-1 s^-1. We find only minor differences in these on rates w

SUBMITTER: Stojanovic P 

PROVIDER: S-EPMC10433523 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature