Effects of the Ser326Cys Polymorphism in the DNA Repair OGG1 Gene on Cancer, Cardiovascular, and All-Cause Mortality in the PREDIMED Study: Modulation by Diet

Corella, Dolores; Sabio, J.B. Ramirez; Coltell, Oscar; Ortega-Azorín, Carolina; Estruch, Ramón; Martínez‐González, Miguel A.; Salas‐Salvadó, Jordi; Sorlí, José V.; Castañer, Olga; Arós, Fernando; Garcia-Corte, Franscisco J.; Serra‐Majem, Lluís; Gómez‐Gracia, Enrique; Fiol, Miquel; Pintó, Xavier; Sáez, Guillermo; Toledo, Estefanía; Basora, Josep; Fitó, Montserrat; Cofán, Montserrat; Ros, Emilio; Ordovás, José M.

doi:10.1016/j.jand.2017.09.025

Cited by 20 publications

(11 citation statements)

References 73 publications

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“…Our results show that the ROS inducer menodione more potently induces type 1 IFN expression from Ogg1 −/− BMDMs, in keeping with the model that lack of Ogg1 results in accumulation of oxidized DNA, driving a more potent activation of the STING-dependent cytoplasmic DNA-sensing pathway. There are 21 known polymorphisms in OGG1, 13 of which are associated with disease due to reduced capacity to repair DNA damage (13,39,40). In addition, OGG1 polymorphisms have been linked to SLE risk.…”

Section: Discussionmentioning

confidence: 99%

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Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

et al. 2020

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Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2 ′-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1 −/− mice showed increased influx of Ly6C hi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1 −/− mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1 −/− mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.

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Section: Discussionmentioning

confidence: 99%

“…There are 21 known polymorphisms in OGG1 , 13 of which are associated with disease due to reduced capacity to repair DNA damage ( 13 , 39 , 40 ). In addition, OGG1 polymorphisms have been linked to SLE risk.…”

Section: Discussionmentioning

confidence: 99%

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

et al. 2020

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“…Similarly, in a Mexican cohort, the Ser326Cys polymorphism was independently correlated with increased incidence of type-2 diabetes [119]. Further, in a recent report from the European PREDIMED study, individuals homozygous for the Cys/Cys genotype had increased total mortality, attributable to cardiovascular disease-related deaths, but not to cancer-related mortality [210]. Together, these data in human populations underscore a role for OGG1 in modulating metabolic risk.…”

Section: Metabolic Diseasementioning

confidence: 97%

Mitochondrial DNA Integrity: Role in Health and Disease

Sharma

Sampath

2019

Cells

165

131

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As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.

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“…Homozygotes of the hOGG1 S326C allele are at elevated risk for developing several types of cancer [10–13] as well as the age-related degenerative disorder, macular degeneration [14]. A longevity study involving 7170 subjects, aged 55 to 70 at high risk for cardiovascular disease was recently reanalyzed for the S326C mutation and cancer, cardiovascular disease, and all-cause mortality [15]. Cys/Cys individuals had a hazard ratio of 1.69 over Ser carriers.…”

Section: Introductionmentioning

confidence: 99%

Enhanced mitochondrial DNA repair of the common disease-associated variant, Ser326Cys, of hOGG1 through small molecule intervention

Baptiste

Katchur

Fivenson

et al. 2018

Free Radical Biology and Medicine

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The common oxidatively generated lesion, 8-oxo-7,8-dihydroguanine (8-oxoGua), is removed from DNA by base excision repair. The glycosylase primarily charged with recognition and removal of this lesion is 8-oxoGuaDNA glycosylase 1 (OGG1). When left unrepaired, 8-oxodG alters transcription and is mutagenic. Individuals homozygous for the less active OGG1 allele, Ser326Cys, have increased risk of several cancers. Here, small molecule enhancers of OGG1 were identified and tested for their ability to stimulate DNA repair and protect cells from the environmental hazard paraquat (PQ). PQ-induced mtDNA damage was inversely proportional to the levels of OGG1 expression whereas stimulation of OGG1, in some cases, entirely abolished its cellular effects. The PQ-mediated decline of mitochondrial membrane potential or nuclear condensation were prevented by the OGG1 activators. In addition, in Ogg1 mouse embryonic fibroblasts complemented with hOGG1, there was increased cellular and mitochondrial reactive oxygen species compared to their wild type counterparts. Mitochondrial extracts from cells expressing hOGG1 were deficient in mitochondrial 8-oxodG incision activity, which was rescued by the OGG1 activators. These data demonstrate that small molecules can stimulate OGG1 activity with consequent cellular protection. Thus, OGG1-activating compounds may be useful in select humans to mitigate the deleterious effects of environmental oxidants and mutagens.

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Effects of the Ser326Cys Polymorphism in the DNA Repair OGG1 Gene on Cancer, Cardiovascular, and All-Cause Mortality in the PREDIMED Study: Modulation by Diet

Abstract: In this population, the Cys326Cys-OGG1 genotype was associated with all-cause mortality, mainly CVD instead of cancer mortality. Additional studies are needed to provide further evidence on its dietary modulation.

Cited by 20 publications

References 73 publications

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

Mitochondrial DNA Integrity: Role in Health and Disease

Enhanced mitochondrial DNA repair of the common disease-associated variant, Ser326Cys, of hOGG1 through small molecule intervention

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