Activity of OGG1 variants in the repair of pro-oxidant-induced 8-oxo-2′-deoxyguanosine

Smart, Daniel J.; Chipman, J.K.; Hodges, Nikolas J.

doi:10.1016/j.dnarep.2006.06.001

Cited by 74 publications

(56 citation statements)

References 51 publications

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“…It has been shown that transgenic expression of OGG1 in Ogg1 −/− cells restored the wild-type phenotype in response to all pro-oxidants tested (Smart et al, 2006). In our hand, overexpression of OGG1 decreased 8-oxoG levels in the DNA and prevented development of H ROS cells in the surviving clones of OGG1 expressing cells.…”

Section: Discussionmentioning

confidence: 60%

Increased ROS generation in subsets of OGG1 knockout fibroblast cells

Bácsi

Chodaczek

Hazra³

et al. 2007

Mechanisms of Ageing and Development

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Oxoguanine DNA glycosylase (OGG1) is a major base excision repair protein responsible for excision of the mutagenic 8-oxoguanosine (8-oxoG) lesions from the genome. Despite OGG1's importance, the moderate phenotype of Ogg1-null (Ogg1 −/− ) mice is not well understood. This study addresses a mechanism by which Ogg1 −/− cells limit accumulation of 8-oxoG in their genome. Our data reveal that a subset of Ogg1 −/− cells shows higher ROS levels ( H ROS cells), while ~85% of Ogg1 −/− cells exhibit physiological levels of ROS ( L ROS cells). Ogg1 −/− cells were sorted based on their DCF fluorescence intensity to obtain L ROS and H ROS cell cultures. L ROS cultures proliferated at a rate comparable to Ogg1 +/+ and gradually accumulated cells exhibiting increased ROS and 8-oxoG levels. L ROS cells show a 2.8-fold increase in 8-oxoG level vs. H ROS cells (7-to 27-fold). Mitochondria of H ROS cells released more H 2 O 2 than L ROS and Ogg1 +/+ cells and were eliminated by apoptotic-like processes. These findings suggest that in the absence of OGG1, a surveillance system is activated that removes cells with extreme 8-oxoG levels from Ogg1 −/− cultures. Whether similar mechanism exists in tissues of Ogg1 −/− mice is the focus of future investigations.

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Section: Discussionmentioning

confidence: 60%

Increased ROS generation in subsets of OGG1 knockout fibroblast cells

Bácsi

Chodaczek

Hazra³

et al. 2007

Mechanisms of Ageing and Development

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“…The most studied is the single nucleotide polymorphism at codon 326 (Ser326Cys). Homozygous carriers of the variant form of the OGG1 Ser326Cys gene appear to have reduced repair capacity for oxidised DNA lesions (31,32), but this association has not been found in all investigations (33).…”

Section: Discussionmentioning

confidence: 99%

The Association of OGG1 Ser326Cys Polymorphism and Urinary 8-OHdG Levels With Lung Cancer Susceptibility: A Hospital-Based Case-Control Study in Turkey

Karahalıl

Emerce

Koçer

et al. 2008

Archives of Industrial Hygiene and Toxicology

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High incidence and poor prognosis of lung cancer make it a major health problem worldwide. Although smoking is a major cause of lung cancer, only some smokers develop lung cancer, which suggests that there is a genetic predisposition in some individuals. 8-OHG is an important oxidative base lesion and may elevate due to cancer and smoking. It is repaired by 8-hydroxyguanine DNA glycosylase 1 (OGG1), which has several polymorphisms. Although the Ser326Cys polymorphism is consistently associated with a range of cancers, findings about this polymorphism and lung cancer risk are contradictory. To date, no study has examined this association in the Turkish population. We conducted a case-control study to investigate the association between OGG1 Ser326Cys polymorphism and the risk of lung cancer using PCR-RFLP. We also evaluated gene-smoking interaction and excretion of urinary 8-OHdG. Our results suggest that the OGG1 Ser326Cys polymorphism is not a genetic risk factor for lung cancer, and that the heterozygous genotype is associated with a significantly reduced risk for lung cancer. The levels of 8-OHdG did not correlate with the polymorphism and smoking. Larger association studies are needed to validate our findings, and mechanistic studies are needed to elucidate the underlying molecular mechanisms of this association.

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“…The steadystate level of 8-oxodG in DNA reflects its rate of generation and of repair. 8-OxodG in DNA is repaired primarily via the DNA base excision repair pathway (17). The DNA repair enzyme that recognizes and excises 8-oxodG is 8-oxoG-DNA glycosylase (OGG1) (18).…”

Section: Conclusion-hyperglycemiamentioning

confidence: 99%

Mechanism of Oxidative DNA Damage in Diabetes

Simone

Gorin²,

Velagapudi³

et al. 2008

Diabetes

115

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OBJECTIVE-To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells. Akt and tuberin, levels, and 8-oxoG-DNA glycosylase (OGG1) expression were measured in kidney cortical tissue of control and type 1 diabetic animals and in proximal tubular cells incubated with normal or high glucose. RESEARCH DESIGN AND METHODS-Phosphorylation ofRESULTS-In the renal cortex of diabetic rats, the increase in Akt phosphorylation is associated with enhanced phosphorylation of tuberin, decreased OGG1 protein expression, and 8-oxodG accumulation. Exposure of proximal tubular epithelial cells to high glucose causes a rapid increase in reactive oxygen species (ROS) generation that correlates with the increase in Akt and tuberin phosphorylation. High glucose also resulted in downregulation of OGG1 protein expression, paralleling its effect on Akt and tuberin. Inhibition of phosphatidylinositol 3-kinase/ Akt significantly reduced high glucose-induced tuberin phosphorylation and restored OGG1 expression. Hydrogen peroxide stimulates Akt and tuberin phosphorylation and decreases OGG1 protein expression. The antioxidant N-acetylcysteine significantly inhibited ROS generation, Akt/protein kinase B, and tuberin phosphorylation and resulted in deceased 8-oxodG accumulation and upregulation of OGG1 protein expression.CONCLUSIONS-Hyperglycemia in type 1 diabetes and treatment of proximal tubular epithelial cells with high glucose leads to phosphorylation/inactivation of tuberin and downregulation of OGG1 via a redox-dependent activation of Akt in renal tubular epithelial cells. This signaling cascade provides a mechanism of oxidative stress-mediated DNA damage in diabetes. Diabetes

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Activity of OGG1 variants in the repair of pro-oxidant-induced 8-oxo-2′-deoxyguanosine

Cited by 74 publications

References 51 publications

Increased ROS generation in subsets of OGG1 knockout fibroblast cells

Increased ROS generation in subsets of OGG1 knockout fibroblast cells

The Association of OGG1 Ser326Cys Polymorphism and Urinary 8-OHdG Levels With Lung Cancer Susceptibility: A Hospital-Based Case-Control Study in Turkey

Mechanism of Oxidative DNA Damage in Diabetes

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