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Molecular and Cellular Biology, August 2001, p. 5605-5613, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5605-5613.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Increased Susceptibility to Streptozotocin-Induced beta -Cell Apoptosis and Delayed Autoimmune Diabetes in Alkylpurine- DNA-N-Glycosylase-Deficient Mice

John W. Cardinal,1 Geoffrey P. Margison,2 Kurt J. Mynett,2 Allen P. Yates,3 Donald P. Cameron,1 and Rhoderick H. Elder2,*

Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, Brisbane 4102, Australia,1 and CRC Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester, M20 4BX,2 and Department of Clinical Biochemistry, Manchester Royal Infirmary, Manchester M13 9WL,3 United Kingdom

Received 15 December 2000/Returned for modification 23 March 2001/Accepted 8 May 2001

Type 1 diabetes is thought to occur as a result of the loss of insulin-producing pancreatic beta  cells by an environmentally triggered autoimmune reaction. In rodent models of diabetes, streptozotocin (STZ), a genotoxic methylating agent that is targeted to the beta  cells, is used to trigger the initial cell death. High single doses of STZ cause extensive beta -cell necrosis, while multiple low doses induce limited apoptosis, which elicits an autoimmune reaction that eliminates the remaining cells. We now show that in mice lacking the DNA repair enzyme alkylpurine-DNA-N-glycosylase (APNG), beta -cell necrosis was markedly attenuated after a single dose of STZ. This is most probably due to the reduction in the frequency of base excision repair-induced strand breaks and the consequent activation of poly(ADP-ribose) polymerase (PARP), which results in catastrophic ATP depletion and cell necrosis. Indeed, PARP activity was not induced in APNG-/- islet cells following treatment with STZ in vitro. However, 48 h after STZ treatment, there was a peak of apoptosis in the beta  cells of APNG-/- mice. Apoptosis was not observed in PARP-inhibited APNG+/+ mice, suggesting that apoptotic pathways are activated in the absence of significant numbers of DNA strand breaks. Interestingly, STZ-treated APNG-/- mice succumbed to diabetes 8 months after treatment, in contrast to previous work with PARP inhibitors, where a high incidence of beta -cell tumors was observed. In the multiple-low-dose model, STZ induced diabetes in both APNG-/- and APNG+/+ mice; however, the initial peak of apoptosis was 2.5-fold greater in the APNG-/- mice. We conclude that APNG substrates are diabetogenic but by different mechanisms according to the status of APNG activity.

* Corresponding author. Mailing address: CRC Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 4BX, United Kingdom. Phone: 44-161-446-3124. Fax: 44-161-446-3109. E-mail: relder{at}picr.man.ac.uk.

Molecular and Cellular Biology, August 2001, p. 5605-5613, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5605-5613.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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