Abstract
PolyADP-ribosylation is a post-translational modification of proteins, and poly(ADP-ribose) (PAR) polymerase (PARP) family proteins synthesize PAR using NAD as a substrate. Poly(ADP-ribose) glycohydrolase (PARG) functions as the main enzyme for the degradation of PAR. In this study, we investigated the effects of Parg deficiency on tumorigenesis and therapeutic efficacy of DNA damaging agents, using mouse ES cell-derived tumor models. To examine the effects of Parg deficiency on tumorigenesis, Parg+/+ and Parg−/− ES cells were subcutaneously injected into nude mice. The results showed that Parg deficiency delays early onset of tumorigenesis from ES cells. All the tumors were phenotypically similar to teratocarcinoma and microscopic findings indicated that differentiation spectrum was similar between the Parg genotypes. The augmented anti-tumor therapeutic effects of X-irradiation were observed under Parg deficiency. These results suggest that Parg deficiency suppresses early stages of tumorigenesis and that Parg inhibition, in combination with DNA damaging agents, may efficiently control tumor growth in particular types of germ cell tumors.
Highlights
PolyADP-ribosylation is the post-translational modification of proteins, and poly(ADP-ribose) glycohydrolase (PARG) is involved in the degradation of PAR as a main enzyme
In this study, using hypomorphic Parg knockout embryonic stem (ES) cells, we investigated the effects of Parg deficiency on tumorigenesis and the therapeutic efficacy of DNA damaging agents using ES
To examine the effects of Parg deficiency on tumorigenesis, Parg+/+ J1 and two D79 and D122 Parg−/− ES cells were subcutaneously injected into the flanks of nude mice
Summary
PolyADP-ribosylation is the post-translational modification of proteins, and poly(ADP-ribose) glycohydrolase (PARG) is involved in the degradation of PAR as a main enzyme. DNA strand breaks and is involved in base-excision repair, DNA strand break repair pathways [1]. The process of polyADP-ribosylation of proteins is tightly regulated by the second enzyme in the metabolic pair: PARG and ADP-ribosyl hydrolase (ARH3) [2]. PARG reverses the action of PARP by hydrolyzing the glycosidic bonds of PAR to produce ADP-ribose [3,4]. The catalytic capacity of PARG keeps the polyADP-ribosylation of proteins transient; the conversion rate of PAR is measured in minutes [1]
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