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Molecular and Cellular Biology, August 2004, p. 7163-7178, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7163-7178.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Ulrich Cortes,1 Wei-Min Tong,1 Donna L. Coyle,2 Mirella L. Meyer-Ficca,2 Ralph G. Meyer,2 Virginie Petrilli,1 Zdenko Herceg,1 Elaine L. Jacobson,2 Myron K. Jacobson,2 and Zhao-Qi Wang1*

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.

* Corresponding author. Mailing address: International Agency for Research on Cancer, 150 cours Albert-Thomas, 69008 Lyon, France. Phone: 33-4-72-73-8510. Fax: 33-4-72-73-8329. E-mail: zqwang{at}iarc.fr.

Molecular and Cellular Biology, August 2004, p. 7163-7178, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.7163-7178.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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