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Essential role of β‐human 8‐oxoguanine DNA glycosylase 1 in mitochondrial oxidative DNA repair
Author(s) -
Su YuHung,
Lee YenLing,
Chen SungFang,
Lee YunPing,
Hsieh YiHsuan,
Tsai JuiHe,
Hsu JyeLin,
Tian WeiTing,
Huang Wenya
Publication year - 2013
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.21742
Subject(s) - mitochondrial dna , dna glycosylase , biology , mitochondrion , dna repair , inner mitochondrial membrane , base excision repair , atp–adp translocase , microbiology and biotechnology , dna damage , biochemistry , dna , gene
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 α‐ and β‐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 β‐ but not α‐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 β‐ but not α‐hOGG1 is localized in the mitochondrial inner membrane. Analyses of nuclear and mtDNA damage showed that the β‐ but not α‐ hogg1 knockdown (KD) cells were severely defective in mitochondrial BER, indicating an essential requirement of β‐hOGG1 for mtDNA repair. β‐ hogg1 KD cells were also found to be mildly deficient in Complex I activity, suggesting that β‐hOGG1 is an accessory factor for the mitochondrial integral function for ATP synthesis. In summary, our findings define β‐hOGG1 as an important factor for mitochondrial BER and as an accessory factor in the mitochondrial Complex I function. Mol. Mutagen. 2013. © 2012 Wiley Periodicals, Inc.