Abstract
Abstract The synthesis of poly(ADP-ribose) (PAR) is an immediate response to DNA damage. We reported previously that the failure to degrade PAR by inhibiting PAR glycohydrolase (PARG) leads to hypersensitivity to DNA damage. To investigate the ability of PARG inhibition to increase the effectiveness of DNA-damaging agents, we analyzed chromatin structure, DNA damage and repair, and cell death in PARG null trophoblast stem cells. PARG null cells displayed high levels of PAR-modified histones H1 and H2B, suggesting chromatin structural change. Chromatin decondensation was observed in PARG null cells by transmission electron microscopy. This structural change led to increased access of the DNA-modifying agent acridine orange and micrococcal nuclease. Analysis by Comet assay demonstrated an extraordinary amount of DNA damage induced by sublethal amounts of the DNA alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine that was subsequently not repaired in PARG null cells. To determine if this chromatin decondensation might lead to enhanced access of DNA to currently utilized DNA-modifying chemotherapeutic agents, PARG null cells were treated with cisplatin and cyclophosphamide. Each induced 2 to 4 folds greater amounts of cell death in PARG null cells. Taken together, the results show that PARG inhibition enhances the efficacy of DNA-damaging agents by inducing a greater amount of DNA damage, a decrease in DNA repair, and an increase in cell death. The results therefore suggest that targeting PARG will enhance the effectiveness of DNA-modifying anti-cancer agents. This research was supported by funding from the American Cancer Society and the Pharmaceutical Research Manufacturers of America. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3931.
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