02 May 2003 : Original article
Functional study of poly(ADP-ribose) glycohydrolase (PARG)U. Cortes, W. Tong, Z. Herceg, V. Petrilli, E. Jacobson, M. Jacobson, Z. Wang
Med Sci Monit 2003; 9(1): 14- :: ID: 15061
Poly(ADP-ribosyl)ation of proteins is one of the earliest responses to DNA damage in most eukaryotic cells. This posttranslational modification of nuclear proteins is achieved by the enzyme poly(ADP-ribose) polymerase (PARP-1), which synthesizes branched polymers of ADP-ribose (pADPr). Poly(ADP-ribose) polymers are then rapidly catabolized by the degrading enzyme poly(ADP-ribose) glycohydrolase (PARG). Although inhibition or depletion of PARP-1 demonstrates that PARP-1 and poly(ADP-ribosyl)ation play a role in cell proliferation and death, stress response, cell toxicity, DNA repair, recombination, and chromosomal stability, the exact functions of poly(ADP-ribosyl)ation and PARP-1 are largely unknown. This may be due to insufficient knowledge about PARG function, since only a few studies regarding pADPr catabolism have been performed. To better define the functions of PARG and poly(ADP-ribosyl)ation in vivo, we disrupted the PARG gene in ES cells by homologous recombination. Intercrossing of PARG heterozygous (PARG+/D) mice produced a normal mendelian ratio of PARG+/+, PARG+/D and PARGD/D offspring. Interestingly, homozygous PARG knockout mice developed normally, and were healthy and fertile. Expression analysis demonstrated the absence of PARG mRNA in PARGD/D cells and mice, and in the PARG+/D cells, PARG expression was at half of that of wild-type counterparts. These data indicate that PARG is not essential for normal development. Detailed analysis of pADPr metabolism in PARGD/D cells and inflammation response of PARGD/D mice indicate that PARG activity is important for controlling PARP-1 activity in vivo, possibly by regulating its auto-modifications.
Keywords: PARG, Poly(ADP-ribosyl)ation, Gene Targeting
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