Essential Role Of Ss-Human 8-Oxoguanine Dna Glycosylase 1 In Mitochondrial Oxidative Dna Repair
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS(2013)
摘要
8-Oxoguanine (8-OG) is the major mutagenic base lesion in DNA caused by reactive oxygen species (ROS) and accumulates in both nuclear and mitochondrial DNA (mtDNA). In humans, 8-OG is primarily removed by human 8-OG DNA glycosylase 1 (hOGG1) through the base excision repair (BER) pathway. There are two major hOGG1 isoforms, designated a- and beta-hOGG1, generated by alternative splicing, and they have distinct subcellular localization: cell nuclei and mitochondria, respectively. Using yeast two-hybrid screening assays, we found that beta- but not a-hOGG1 directly interacts with the mitochondrial protein NADH:ubiquinone oxidoreductase 1 beta subcomplex 10 (NDUFB10), an integral factor in Complex 1 on the mitochondrial inner membrane. Using coimmunoprecipitation and immunofluorescence studies, we found that this interaction was greatly increased by hydrogen peroxide-induced oxidative stress, suggesting that beta- but not a-hOGG1 is localized in the mitochondrial inner membrane. Analyses of nuclear and mtDNA damage showed that the beta- but not a- hogg1 knockdown (KD) cells were severely defective in mitochondrial BER, indicating an essential requirement of beta-hOGG1 for mtDNA repair. beta-hogg1 KD cells were also found to be mildly deficient in Complex I activity, suggesting that beta-hOGG1 is an accessory factor for the mitochondrial integral function for ATP synthesis. In summary, our findings define beta-hOGG1 as an important factor for mitochondrial BER and as an accessory factor in the mitochondrial Complex I function. Mol. Mutagen. 2013. (c) 2012 Wiley Periodicals, Inc.
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关键词
8-oxoguanine, 8-oxoguanine glycosylase, mitochondria, oxidative DNA repair, base excision repair
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