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Originally published In Press as doi:10.1074/jbc.M000831200 on September 11, 2000

J. Biol. Chem., Vol. 275, Issue 48, 37518-37523, December 1, 2000
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Enhanced Mitochondrial DNA Repair and Cellular Survival after Oxidative Stress by Targeting the Human 8-Oxoguanine Glycosylase Repair Enzyme to Mitochondria*

Allison W. DobsonDagger , Yi Xu§, Mark R. Kelley§, Susan P. LeDouxDagger , and Glenn L. WilsonDagger

From the Dagger  Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, Alabama 36688, and § Department of Pediatrics, Wells Center for Pediatric Research, Indiana University Medical School, Indianapolis, Indiana 46202

Oxidative damage to mitochondrial DNA (mtDNA) has been implicated as a causative factor in many disease processes and in aging. We have recently discovered that different cell types vary in their capacity to repair this damage, and this variability correlates with their ability to withstand oxidative stress. To explore strategies to enhance repair of oxidative lesions in mtDNA, we have constructed a vector containing a mitochondrial transport sequence upstream of the sequence for human 8-oxoguanine DNA glycosylase. This enzyme is the glycosylase/AP lyase that participates in repair of purine lesions, such as 8-oxoguanine. Western blot analysis confirmed that this recombinant protein was targeted to mitochondria. Enzyme activity assays showed that mitochondrial extracts from cells transfected with the construct had increased enzyme activity compared with cells transfected with vector only, whereas nuclear enzyme activity was not changed. Repair assays showed that there was enhanced repair of oxidative lesions in mtDNA. Additional studies revealed that this augmented repair led to enhanced cellular viability as determined by reduction of the tetrazolium compound to formazan, trypan blue dye exclusion, and clonogenic assays. Therefore, targeting of DNA repair enzymes to mitochondria may be a viable approach for the protection of cells against some of the deleterious effects of oxidative stress.

* This research was supported by National Institutes of Health Grants ES03456, ES05865, and AG12422.The costs of publication of this article were defrayed in part by the payment of page charges. The 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.: 334-460-6765; Fax: 334- 414-8241; E-mail: gwilson@usamail.usouthal.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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