Poly(ADP-ribosyl)ation Pathways in Mammals: The Advantage of Murine PARG Null Mutation

Abstract

Studies suggest that inhibiting the hydrolysis of poly(ADP-ribose) (PAR) by targeting the enzyme PAR glycohydrolase (PARG) is a potential chemotherapeutic strategy to induce cell death. However, the lack of structural data for PARG has hindered the discovery of specific PARG inhibitors and thus hampered the search for cellular effects dependent on the hydrolysis of PAR. We previously generated a murine PARG null cell model to identify the intracellular processes mediated by PARG. Using this system, the only mammalian system to date that completely lacks PARG activity, we have shown that the absence of PARG leads to massive amounts of cell death due to increased levels of PAR. Further, we have shown that PARG null-TS cells exhibit profound hypersensitivity to low doses of DNA-damaging agents. This hypersensitivity most likely results from the high levels of DNA damage that occur after treatment of these cells with nonlethal doses of DNA-damaging agents.