Essential role of β-human 8-oxoguanine DNA glycosylase 1 in mitochondrial oxidative DNA repair

Yu Hung Su, Yen Ling Lee, Sung-Fang Chen, Yun Ping Lee, Yi Hsuan Hsieh, Jui He Tsai, Jye Lin Hsu, Wei Ting Tian, Wenya Huang

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17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)54-64
Number of pages11
JournalEnvironmental and Molecular Mutagenesis
Volume54
Issue number1
DOIs
Publication statusPublished - 2013 Jan 1

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Keywords

  • 8-oxoguanine
  • 8-oxoguanine glycosylase
  • Base excision repair
  • Mitochondria
  • Oxidative DNA repair

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

Cite this

Su, Y. H., Lee, Y. L., Chen, S-F., Lee, Y. P., Hsieh, Y. H., Tsai, J. H., Hsu, J. L., Tian, W. T., & Huang, W. (2013). Essential role of β-human 8-oxoguanine DNA glycosylase 1 in mitochondrial oxidative DNA repair. Environmental and Molecular Mutagenesis, 54(1), 54-64. https://doi.org/10.1002/em.21742