Strategic Combination of DNA-Damaging Agent and PARP Inhibitor Results in Enhanced Cytotoxicity.


PARP inhibitors (PARPi) are under clinical trial for combination ...
PARP inhibitors (PARPi) are under clinical trial for combination cancer chemotherapy. In the presence of a PARPi, PARP-1 binds DNA strand breaks but cannot produce poly(ADP-ribose) polymers or undergo auto-poly(ADP-ribosyl)ation. DNA binding is persistent, hindering DNA repair. Methylated bases formed as a result of cellular exposure to DNA-methylating agents are repaired by DNA polymerase β (pol β)-dependent base excision repair (BER) producing a 5'-deoxyribose phosphate (5'-dRP) repair intermediate. PARP-1 binds and is activated by the 5'-dRP, and PARPi-mediated sensitization to methylating agents is considerable, especially in pol β-deficient cells. Cells deficient in the BER factor XRCC1 are less sensitized by PARPi than are wild-type cells. PARPi sensitization is reduced in cells expressing forms of XRCC1 deficient in interaction with either pol β or PARP-1. In contrast, agents producing oxidative DNA damage and 3'- rather than 5'-repair intermediates are modestly PARPi sensitized. We summarize PARPi experiments in mouse fibroblasts and confirm the importance of the 5'-dRP repair intermediate and functional pol β and XRCC1 proteins. Understanding the chemistry of repair is key to enhancing the clinical success of PARPi.




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