Abstract
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.
Highlights
Clinical trials suggest that PARP inhibitors (PARPi) may represent an opportunity to gain selective killing of cancer cells, since the cytotoxic effects make use of deficiencies in cellular DNA repair systems that are distinctive for individual tumor cells versus normal tissues [1, 2]
We suggest that understanding PARPi effects in model systems, such as mouse embryonic fibroblast (MEF) cells in culture, will be informative for considering strategies in cancer chemotherapy
We have proposed that the DNA-bound and inhibited PARP-1 molecule results in cytotoxicity due to formation of replication-dependent double-strand breaks (DSBs) [14]
Summary
Clinical trials suggest that PARP inhibitors (PARPi) may represent an opportunity to gain selective killing of cancer cells, since the cytotoxic effects make use of deficiencies in cellular DNA repair systems that are distinctive for individual tumor cells versus normal tissues [1, 2]. The level of cell killing observed with DNA-damaging agents is modulated by cotreatment with a PARPi and by expression of other BER proteins such as XRCC1 and pol β, and we will outline a model to explain these effects. It can bind to AP sites and single-strand breaks in DNA, including the 5 -dRP-containing intermediate of BER of MMS-induced damage.
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