Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

Sampath, Harini

doi:10.1002/em.21886

Cited by 34 publications

(44 citation statements)

References 139 publications

(243 reference statements)

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“…Since we have previously reported that Ogg1 -/- mice have impaired insulin sensitivity [28], and given that OGG1 is involved in repair of both genomic, as well as mtDNA [5,49], we were interested in determining the role of OGG1 deficiency on mitochondrial content in the muscle of these animals. There were no differences in total content of mtDNA between genotypes, as measured by qPCR against several different mtDNA target regions (Fig 2A).…”

Section: Resultsmentioning

confidence: 99%

8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle

et al. 2017

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Oxidative stress resulting from endogenous and exogenous sources causes damage to cellular components, including genomic and mitochondrial DNA. Oxidative DNA damage is primarily repaired via the base excision repair pathway that is initiated by DNA glycosylases. 8-oxoguanine DNA glycosylase (OGG1) recognizes and cleaves oxidized and ring-fragmented purines, including 8-oxoguanine, the most commonly formed oxidative DNA lesion. Mice lacking the OGG1 gene product are prone to multiple features of the metabolic syndrome, including high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Here, we report that OGG1-deficient mice also display skeletal muscle pathologies, including increased muscle lipid deposition and alterations in genes regulating lipid uptake and mitochondrial fission in skeletal muscle. In addition, expression of genes of the TCA cycle and of carbohydrate and lipid metabolism are also significantly altered in muscle of OGG1-deficient mice. These tissue changes are accompanied by marked reductions in markers of muscle function in OGG1-deficient animals, including decreased grip strength and treadmill endurance. Collectively, these data indicate a role for skeletal muscle OGG1 in the maintenance of optimal tissue function.

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Section: Resultsmentioning

confidence: 99%

8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle

et al. 2017

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“…We postulate that increased levels of 8-oxoG in AgNP-treated wild type mice is in part due to downregulation of DNA glycosylases that are involved in the repair of 8-oxoG. Ogg1, Neil1, and Neil2 are bifunctional DNA glycosylases with DNA glycosylase and AP lyase activities and have overlapping physiological substrates (Hazra et al 2007; Jacobs and Schar 2012; Sampath 2014). The common substrates recognized by Ogg1, Neil1, and Neil2 are 8-oxoG and FapyG.…”

Section: Discussionmentioning

confidence: 99%

“…8-Oxoguanine DNA glycosylase 1 (OGG1) is a base excision repair (BER) enzyme that removes oxidatively damaged guanine from double stranded DNA (Hirano 2008; Sampath 2014). OGG1 is a bifunctional glycosylase that exhibits DNA glycosylase and apurinic/apyrimidinic (AP) lyase activities.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, in proliferating cells, oxidative DNA damage can result in DSBs and genome rearrangements (deletions, translocations or duplications) via intermediate SSBs (Obe et al 2002). Major substrates of the OGG1 enzyme are 8-oxo-7,8-dihydro-2-deoxyguanine (8-oxoG) and the formamidopyrimidine derivative of guanine (FapyG) (Hazra et al 2007; Sampath 2014). 8-oxoG and FapyG form from a common intermediate during oxidative modification of guanine and both are pro-mutagenic lesions that can result in point mutations (Greenberg 2012).…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of silver nanoparticles on DNA damage and DNA repair gene expression in Ogg1-deficient and wild type mice

et al. 2017

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Due to extensive use in consumer goods, it is important to understand the genotoxicity of silver nanoparticles (AgNPs) and identify susceptible populations. 8-Oxoguanine DNA glycosylase 1 (OGG1) excises 8-oxo-7,8-dihydro-2-deoxyguanine (8-oxoG), a pro-mutagenic lesion induced by oxidative stress. To understand whether defects in OGG1 is a possible genetic factor increasing an individual’s susceptibly to AgNPs, we determined DNA damage, genome rearrangements, and expression of DNA repair genes in Ogg1-deficient and wild type mice exposed orally to 4 mg/kg of citrate-coated AgNPs over a period of 7 d. DNA damage was examined at 3 and 7 d of exposure and 7 and 14 d post-exposure. AgNPs induced 8-oxoG, double strand breaks (DSBs), chromosomal damage, and DNA deletions in both genotypes. However, 8-oxoG was induced earlier in Ogg1-deficient mice and 8-oxoG levels were higher after 7-d treatment and persisted longer after exposure termination. AgNPs downregulated DNA glycosylases Ogg1, Neil1, and Neil2 in wild type mice, but upregulated Myh, Neil1, and Neil2 glycosylases in Ogg1-deficient mice. Neil1 and Neil2 can repair 8-oxoG. Thus, AgNP-mediated downregulation of DNA glycosylases in wild type mice may contribute to genotoxicity, while upregulation thereof in Ogg1-deficient mice could serve as an adaptive response to AgNP-induced DNA damage. However, our data show that Ogg1 is indispensable for the efficient repair of AgNP-induced damage. In summary, citrate-coated AgNPs are genotoxic in both genotypes and Ogg1 deficiency exacerbates the effect. These data suggest that humans with genetic polymorphisms and mutations in OGG1 may have increased susceptibility to AgNP-mediated DNA damage.

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“…The human NTHL1 enzyme is a bifunctional glycosylase involved in the excision of oxidized DNA bases such as Tg, 5‐hydroxycytosine (5‐hC), 5‐hydroxyuracil (5‐hU), and the ring‐opened 2,6‐diamino‐4‐hydroxy‐5‐formamidopyrimidine (Fapy) lesions (Table ). Whereas human NTHL1 is found in both nucleus and mitochondria, mouse Nth1 translocates primarily to the mitochondria [Sampath, ].…”

Section: Dna Glycosylase Families In the Mitochondria: Biochemical Fumentioning

confidence: 99%

Base Excision Repair in the Mitochondria

Prakash

Doublié

2015

J of Cellular Biochemistry

119

110

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The 16.5 kb human mitochondrial genome encodes for 13 polypeptides, 22 tRNAs and 2 rRNAs involved in oxidative phosphorylation. Mitochondrial DNA (mtDNA), unlike its nuclear counterpart, is not packaged into nucleosomes and is more prone to the adverse effects of reactive oxygen species (ROS) generated during oxidative phosphorylation. The past few decades have witnessed an increase in the number of proteins observed to translocate to the mitochondria for the purposes of mitochondrial genome maintenance. The mtDNA damage produced by ROS, if not properly repaired, leads to instability and can ultimately manifest in mitochondrial dysfunction and disease. The base excision repair (BER) pathway is employed for the removal and consequently the repair of deaminated, oxidized, and alkylated DNA bases. Specialized enzymes called DNA glycosylases, which locate and cleave the damaged base, catalyze the first step of this highly coordinated repair pathway. This review focuses on members of the four human BER DNA glycosylase superfamilies and their subcellular localization in the mitochondria and/or the nucleus, as well as summarizes their structural features, biochemical properties, and functional role in the excision of damaged bases.

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Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

Cited by 34 publications

References 139 publications

8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle

8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle

Differential effects of silver nanoparticles on DNA damage and DNA repair gene expression in Ogg1-deficient and wild type mice

Base Excision Repair in the Mitochondria

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