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J. Biol. Chem., Vol. 280, Issue 10, 8901-8905, March 11, 2005

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Contribution of Mitochondrial DNA Repair to Cell Resistance from Oxidative Stress^*

Valentina I. Grishko, Lyudmila I. Rachek, Douglas R. Spitz¶, Glenn L. Wilson, and Susan P. LeDoux||

From the Departments of Orthopedics and Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, Alabama 36688 and the ^¶Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242

Numerous studies have revealed that a part of the cellular response to chronic oxidative stress involves increased antioxidant capacity. However, another defense mechanism that has received less attention is DNA repair. Because of the important homeostatic role of mitochondria and the exquisite sensitivity of mitochondrial DNA (mtDNA) to oxidative damage, we hypothesized that mtDNA repair plays an important role in the protection against oxidative stress. To test this hypothesis mtDNA damage and repair was evaluated in normal HA1 Chinese hamster fibroblasts and oxidative stress-resistant variants isolated following chronic exposure to H₂O₂ or 95% O_2. Reactive oxygen species were generated enzymatically using xanthine oxidase and hypoxanthine. When treated with xanthine oxidase reduced levels of initial mtDNA damage and enhanced mtDNA repair were observed in the cells from the oxidative stress-resistant variants, relative to the parental cell line. This enhanced mtDNA repair correlated with an increase in mitochondrial apurinic/apyrimidinic endonuclease activity in both H₂O₂- and O₂-resistant HA1 variants. This is the first report showing enhanced mtDNA repair in the cellular response to chronic oxidative stress. These results provide further evidence for the crucial role that mtDNA repair pathways play in protecting cells against the deleterious effects of reactive oxygen species.

Received for publication, November 17, 2004 , and in revised form, December 21, 2004.

^* This work was supported by National Institutes of Health Grants ES03456, ES05865, CA100045, and AG19602. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 251-460-6762; Fax: 251-414-8241; E-mail: sledoux{at}usouthal.edu.

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