INVESTIGATION OF POLY(ADP-RIBOSE) GLYCOHYDROLASE (PARG) IN CANCER: DISCOVERY OF NOVEL TARGETS TO IMPROVE CHEMOTHERAPY
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Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme that catalyzes the hydrolysis of poly(ADP-ribose) (PAR), which is synthesized by poly(ADP-ribose) polymerases (PARPs) to modify cellular proteins. PARG participates in a number of biological processes, including chromatin dynamics, transcriptional regulation, DNA damage repair, and cell death. However, compared with the established chemotherapeutic potential of inhibiting PAR synthesis by targeting the PARPs, the significance of PARG as a therapeutic target in cancer remains to be elucidated. The first chapter is a literature review of the current knowledge of PARG with a focus on its roles in DNA repair and cell death. In this section, the PAR mediated cell death pathway, Parthanatos, is introduced. Proteins that participate in this pathway including PARP-1, PARG, apoptosis-inducing factor (AIF) and the transient receptor potential, melastatin-2 (TRPM2) Ca2+ channel are discussed. To investigate their roles following DNA damage, we utilized genetic knockout, RNA interference or pharmacological inhibitors to silence PARG and other related proteins. We provide evidence that: 1) the absence of PAR hydrolysis due to the absence of PARG results in the vulnerability of DNA to damaging agents, decreased caspase activity and enhanced AIF mediated cell death; 2) inhibition of both PARP-1 and PARG does not lead to synergistic cell death; 3) silencing of AIF shows the ability of AIF to substitute as a primary mediator of breast cancer cell death in the absence of caspases; and 4) TRPM2 differentially regulates cell proliferation in non-cancerous versus cancerous cells. The inhibition of TRPM2 in breast cancer cells impaired cell growth and greatly enhanced cell death in the presence of chemotherapeutic agents. Thus, by investigating the molecular mechanism of cell death mediated by PAR/PARG, we conclude that the induction of cell death mediated by AIF or specific targeting of TRPM2, has the great potential in chemotherapy to optimize the eradication of breast cancer cells.