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

Research output: Contribution to journalArticle

16 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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DNA Glycosylases
Mitochondrial DNA
DNA Repair
Mitochondrial Membranes
Electron Transport Complex I
Two-Hybrid System Techniques
Mitochondrial Proteins
Alternative Splicing
7,8-dihydro-8-oxoguanine
human oxoguanine glycosylase 1
Cell Nucleus
Human Activities
Hydrogen Peroxide
DNA Damage
Fluorescent Antibody Technique
Reactive Oxygen Species
Mitochondria
Protein Isoforms
Oxidative Stress
Adenosine Triphosphate

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

Essential role of β-human 8-oxoguanine DNA glycosylase 1 in mitochondrial oxidative DNA repair. / Su, Yu Hung; Lee, Yen Ling; Chen, Sung-Fang; Lee, Yun Ping; Hsieh, Yi Hsuan; Tsai, Jui He; Hsu, Jye Lin; Tian, Wei Ting; Huang, Wenya.

In: Environmental and Molecular Mutagenesis, Vol. 54, No. 1, 01.01.2013, p. 54-64.

Research output: Contribution to journalArticle

Su, Yu Hung ; Lee, Yen Ling ; Chen, Sung-Fang ; Lee, Yun Ping ; Hsieh, Yi Hsuan ; Tsai, Jui He ; Hsu, Jye Lin ; Tian, Wei Ting ; Huang, Wenya. / Essential role of β-human 8-oxoguanine DNA glycosylase 1 in mitochondrial oxidative DNA repair. In: Environmental and Molecular Mutagenesis. 2013 ; Vol. 54, No. 1. pp. 54-64.
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AU - Lee, Yen Ling

AU - Chen, Sung-Fang

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AU - Hsieh, Yi Hsuan

AU - Tsai, Jui He

AU - Hsu, Jye Lin

AU - Tian, Wei Ting

AU - Huang, Wenya

PY - 2013/1/1

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N2 - 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.

AB - 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.

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