Poly (ADP-ribose) glycohydrolase (PARG) is the main enzyme that degrades poly(ADP-ribose)(PAR) synthesized by PARP family proteins. It has been reported that dysfunction of PARG induced a delay in DNA repair and cell death accompanying accumulation of PAR in cancer cells. PARG knockdown sensitized to alkylating agents, cisplatin and radiation in certain cancer cell lines. For these reasons, we thought that PARG is a potential druggable target for cancer therapy. Previously, we identified DUSP22 as a novel synthetic lethal gene of PARG dysfunction by comprehensive analysis. In this study, we analyzed the action mechanism of synthetic lethality in the PARG and DUSP22 knocked down cancer cells.
              Double knockdown of DUSP22 and PARG decreased the cell survival as compared with single knockdown in three lung cancer cell lines, A549, SBC5 and PC14. In these cell lines, double knockdown of PARG and DUSP22 significantly increased the subG1 fraction and showed high expression levels of apoptosis-related genes. Additionally, PARG and DUSP22 knocked down A549 cells suppressed the tumor growth in mouse xenograft model. These results suggest that DUSP22 deficiency induces a synthetic lethal effect under PARG inhibition in lung cancer cells and DUSP22 may be a useful biomarker for cancer therapy with PARG inhibitor. Collaborators: Miyuki Hozumi, Yasufumi Murakami, Kazuto Ashizawa, Kengo Inoue.