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Papers In Press, published online ahead of print June 22, 2003
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224
Corresponding Author: vbohr{at}nih.gov
Mitochondrial DNA is constantly exposed to high levels of endogenously produced reac-tive oxygen species, resulting in elevated levels of oxidative damaged DNA bases. A large spectrum of DNA base alterations can be detected after oxidative stress, and many of these are highly mutagenic. Thus, an efficient repair of these is necessary for survival. Some of the DNA repair pathways involved have been characterized, but others are not yet determined. A DNA repair activity for thymine glycol and other oxidized pyrimidines has been described in mammalian mitochondria, but the nature of the glycosylases involved in this pathway remains unclear. The generation of mouse strains lacking mNTH1 and/or mOGG1, the two major DNA N-glycosylase/AP-lyases involved in the repair of oxidative base damage in the nucleus, has provided very useful biological model systems for the study of the function of these and other glycosylases in mitochondrial DNA repair. In this study, mouse liver mitochondrial extracts were generated from mNTH1, mOGG1 - deficient mice, in order to ascertain the role of each of these glycosy-lases in the repair of oxidized pyrimidine base damage. We also characterized for the first time the incision of various modified bases in mitochondrial extracts from the double knockout, [mNTH1, mOGG1]-deficient, mouse. We demonstrate that mNTH1 is the only glycosylase/AP lyase responsible for the repair of thymine glycols in mitochondrial DNA, while other glycosylase/AP lyases also participate in removing other oxidized pyrimidi-nes, such as 5-hydroxycytosine and 5-hydroxyuracil. We did not detect a backup glyco-sylase or glycosylase/AP lyase activity for thymine glycol in the mitochondrial mouse ex-tracts.
J. Biol. Chem, 10.1074/jbc.M301617200
Submitted on February 14, 2003
Revised on June 22, 2003
Accepted on June 22, 2003
Compromised incision of oxidized pyrimidines in liver mitochondria of mice deficient in NTH1 and OGG1 glycosylases
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