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Depletion of the 110-Kilodalton Isoform of Poly(ADP-Ribose) Glycohydrolase Increases Sensitivity to Genotoxic and Endotoxic Stress in Mice

International Agency for Research on Cancer, 69008 Lyon, France,¹ Department of Pharmacology and Toxicology, College of Pharmacy, and Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724²

Received 12 March 2004/ Returned for modification 22 April 2004/ Accepted 14 May 2004

Poly(ADP-ribosylation) is rapidly stimulated in cells following DNA damage. This posttranslational modification is regulated by the synthesizing enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the degrading enzyme poly(ADP-ribose) glycohydrolase (PARG). Although the role of PARP-1 in response to DNA damage has been studied extensively, the function of PARG and the impact of poly(ADP-ribose) homeostasis in various cellular processes are largely unknown. Here we show that by gene targeting in embryonic stem cells and mice, we specifically deleted the 110-kDa PARG protein (PARG₁₁₀) normally found in the nucleus and that depletion of PARG₁₁₀ severely compromised the automodification of PARP-1 in vivo. PARG₁₁₀-deficient mice were viable and fertile, but these mice were hypersensitive to alkylating agents and ionizing radiation. In addition, these mice were susceptible to streptozotocin-induced diabetes and endotoxic shock. These data indicate that PARG₁₁₀ plays an important role in DNA damage responses and in pathological processes.

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