Impact of a Cancer-Associated Mutation on Poly(ADP-ribose) Polymerase1 Inhibition.

Abstract

Poly(ADP-ribose) polymerase1 (PARP1) plays a vital role in DNA repair, and its inhibition in cancer cells may cause cell apoptosis. In this study, we investigated the effects of a PARP1 variant, V762A, which is strongly associated with several cancers in humans, on the inhibition of PARP1 by three FDA-approved inhibitors: niraparib, rucaparib, and talazoparib. Specifically, we compared the inhibition of the mutant to that of wild-type (WT) PARP1. Additionally, we investigated how the mutation influences the binding of these inhibitors to PARP1. Our work suggests that while mutant PARP1 exhibits only minor differences in residual fluctuations, backbone deviations, and residue motion correlations compared to the WT under niraparib and rucaparib inhibitions, it shows significant and distinct differences in these features when inhibited by talazoparib. Among the three inhibitions, talazoparib inhibition uniquely lowers the average residue fluctuations in the mutant than the WT including lower fluctuations of mutant's N- and C-terminal residues in the catalytic domain, conserved H-Y-E traid residues, and donor loop (D-loop) residues which are important for catalysis more effectively than other inhibitions. However, talazoparib also significantly enhances destabilizing interactions between the mutation site in the HD domain in the mutant than WT. Further, among the three inhibitions, talazoparib inhibition uniquely and significantly disrupts the functional fluctuations of terminal regions in the mutant, which are otherwise present in the WT. The mutation and inhibition do not significantly affect PARP1's essential dynamics. Lastly, these inhibitors bind to the V762A mutant more effectively than to the WT, with similar binding free energies between them.