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Nucleic Acids Research, 2002, Vol. 30, No. 13 2817-2824
© 2002 Oxford University Press

The mitochondrial DNA polymerase as a target of oxidative damage

Maria A. Graziewicz, Brian J. Day1 and William C. Copeland*

Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, PO Box 12233, 111 TW Alexander Drive, Research Triangle Park, NC 27709, USA and 1 National Jewish Medical and Research Center, Department of Medicine, 1400 Jackson Street, Goodman Building, Room 70, Denver, CO 80206, USA

The mitochondrial respiratory chain is a source of reactive oxygen species (ROS) that are responsible for oxidative modification of biomolecules, including proteins. Due to its association with mitochondrial DNA, DNA polymerase {gamma} (pol {gamma}) is in an environment to be oxidized by hydrogen peroxide and hydroxyl radicals that may be generated in the presence of iron ions associated with DNA. We tested whether human pol {gamma} was a possible target of ROS with H2O2 and investigated the effect on the polymerase activities and DNA binding efficiency. A 1 h treatment with 250 µM H2O2 significantly inhibited DNA polymerase activity of the p140 subunit and lowered its DNA binding efficiency. Addition of p55 to the p140 catalytic subunit prior to H2O2 treatment offered protection from oxidative inactivation. Oxidatively modified amino acid residues in pol {gamma}  resulting from H2O2 treatment were observed in vitro as well as in vivo, in SV40-transfected human fibroblasts. Pol {gamma} was detected as one of the major oxidized mitochondrial matrix proteins, with a detectable decline in polymerase activity. These results suggest pol {gamma} as a target of oxidative damage, which may result in a reduction in mitochondrial DNA replication and repair capacities.

* To whom correspondence should be addressed. Tel: +1 919 541 4792; Fax: +1 919 541 7613; Email: copelan1{at}niehs.nih.gov Permanent address:Maria A. Graziewicz, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskieo Street 02-106 Warsaw, Poland


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