1. Free Radical Biology and Medicine. 2018 Aug 20; 124: 149–162.
Enhanced Mitochondrial DNA Repair of the Common Disease- Associated Variant, Ser326Cys, of hOGG1 through Small Molecule Intervention.
Beverly A. Baptiste,a Steven R. Katchur,b Elayne M. Fivenson,a Deborah L. Croteau,a William L. Rumsey,b and Vilhelm A. Bohr,a.
a Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD
b Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, PA
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 hOGG1S326C, there was increased cellular and mitochondrial reactive oxygen species compared to their wild type counterparts. Mitochondrial extracts from cells expressing hOGG1S326C 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.
2. Science Reports. 2018 Oct 5;8(1):14886.
The DNA Repair Protein OGG1 Protects Against Obesity by Altering Mitochondrial Energetics in White Adipose Tissue.
Komakula SSB1,2, Tumova J1, Kumaraswamy D1, Burchat N1, Vartanian V3, Ye H1, Dobrzyn A2, Lloyd RS3, Sampath H4.
1. Department of Nutritional Sciences and Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA.
2. Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Warsaw, Poland.
3. Oregon Institute of Occupational Health Sciences, Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA.
4. Department of Nutritional Sciences and Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, USA.
Obesity and related metabolic pathologies represent a significant public health concern. Obesity is associated with increased oxidative stress that damages genomic and mitochondrial DNA. Oxidatively-induced lesions in both DNA pools are repaired via the base-excision repair pathway, initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). Global deletion of OGG1 and common OGG1 polymorphisms render mice and humans susceptible to metabolic disease. However, the relative contribution of mitochondrial OGG1 to this metabolic phenotype is unknown. Here, we demonstrate that transgenic targeting of OGG1 to mitochondria confers significant protection from diet-induced obesity, insulin resistance, and adipose tissue inflammation. These favorable metabolic phenotypes are mediated by an increase in whole body energy expenditure driven by specific metabolic adaptations, including increased mitochondrial respiration in white adipose tissue of OGG1 transgenic (Ogg1Tg) animals. These data demonstrate a critical role for a DNA repair protein in modulating mitochondrial energetics and whole-body energy balance
3. DNA Repair (Amst). 2019 Sep;81:102667.
Roles of OGG1 in transcriptional regulation and maintenance of metabolic homeostasis.
Sampath H1, Lloyd RS2.
1. Department of Nutritional Sciences and New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, 08901, United States.
2. Oregon Institute for Occupational Health Sciences, Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, Oregon, 97239, United States.
Cellular damage produced by conditions generating oxidative stress have far-reaching implications in human disease that encompass, but are not restricted to aging, cardiovascular disease, type 2 diabetes, airway inflammation/asthma, cancer, and metabolic syndrome including visceral obesity, insulin resistance, fatty liver disease, and dyslipidemia. Although there are numerous sources and cellular targets of oxidative stress, this review will highlight literature that has investigated downstream consequences of oxidatively-induced DNA damage in both nuclear and mitochondrial genomes. The presence of such damage can in turn, directly and indirectly modulate cellular transcriptional and repair responses to such stressors. As such, the persistence of base damage can serve as a key regulator in coordinated gene-response cascades. Conversely, repair of these DNA lesions serves as both a suppressor of mutagenesis and by inference carcinogenesis, and as a signal for the cessation of ongoing oxidative stress. A key enzyme in all these processes is 8-oxoguanine DNA glycosylase (OGG1), which, via non-catalytic binding to oxidatively-induced DNA damage in promoter regions, serves as a nucleation site around which changes in large-scale regulation of inflammation-associated gene expression can occur. Further, the catalytic function of OGG1 can alter the three-dimensional structure of specialized DNA sequences, leading to changes in transcriptional profiles. This review will concentrate on adverse deleterious health effects that are associated with both the diminution of OGG1 activity via population-specific polymorphic variants and the complete loss of OGG1 in murine models. This mouse model displays diet- and age-related induction of metabolic syndrome, highlighting a key role for OGG1 in protecting against these phenotypes. Conversely, recent investigations using murine models having enhanced global expression of a mitochondrial-targeted OGG1 demonstrate that they are highly resistant to diet-induced disease. These data suggest strategies through which therapeutic interventions could be designed for reducing or limiting adverse human health consequences to these ubiquitous stressors.
4. PLOS One, January 14, 2020.
OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model.
Holly Simon1, Vladimir Vartanian2, Melissa H. Wong3,4, Yusaku Nakabeppu5 , Priyanka Sharma6,7, R. Stephen Lloyd2,4,8, Harini Sampath6,7.
1. Division of Environmental and Biomolecular Systems, Institute of Environmental Health, Oregon Health & Science University, Portland, Oregon, United States of America;
2. Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, United States of America;
3. Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America;
4. Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America;
5. Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Fukuoka, Kyushu, Japan;
6. Department of Nutritional Sciences, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America;
7. New Jersey Institute for Food, Nutrition, and Health, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America;
8. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, United States of America.
OGG1-deficient (Ogg1-/-) animals display increased propensity to age-induced and diet-induced metabolic diseases, including insulin resistance and fatty liver. Since the intestinal microbiome is increasingly understood to play a role in modulating host metabolic responses, we examined gut microbial composition in Ogg1-/- mice subjected to different nutritional challenges. Interestingly, Ogg1-/- mice had a markedly altered intestinal microbiome under both control-fed and hypercaloric diet conditions. Several microbial species that were increased in Ogg1-/- animals were associated with increased energy harvest, consistent with their propensity to high-fat diet induced weight gain. In addition, several pro-inflammatory microbes were increased in Ogg1-/- mice. Consistent with this observation, Ogg1-/- mice were significantly more sensitive to intestinal inflammation induced by acute exposure to dextran sulfate sodium. Taken together, these data indicate that in addition to their proclivity to obesity and metabolic disease, Ogg1-/- mice are prone to colonic inflammation. Further, these data point to alterations in the intestinal microbiome as potential mediators of the metabolic and intestinal inflammatory response in Ogg1-/- mice.
5. International Journal of Molecular Sciences, 2021; 22: 1152.
A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis.
Sai Santosh Babu Komakula 1,2, Bhavya Blaze 1,3, Hong Ye 1, Agnieszka Dobrzyn 2 and Harini Sampath 1,3,4.
1. Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA;
2. Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;
3. Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
4. Center for Microbiome, Nutrition, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA
Cells sustain constant oxidative stress from both exogenous and endogenous sources. When unmitigated by antioxidant defenses, reactive oxygen species damage cellular macromolecules, including DNA. Oxidative lesions in both nuclear and mitochondrial DNA are repaired via the base excision repair (BER) pathway, initiated by DNA glycosylases. We have previously demonstrated that the BER glycosylase 8-oxoguanine DNA glycosylase (OGG1) plays a novel role in body weight maintenance and regulation of adiposity. Specifically, mice lacking OGG1 (Ogg1−/−) are prone to increased fat accumulation with age and consumption of hypercaloric diets. Conversely, transgenic animals with mitochondrially-targeted overexpression of OGG1 (Ogg1Tg) are resistant to age- and diet-induced obesity. Given these phenotypes of altered adiposity in the context of OGG1 genotype, we sought to determine if OGG1 plays a cell-intrinsic role in adipocyte maturation and lipid accumulation. Here, we report that preadipocytes from Ogg1−/− mice differentiate more efficiently and accumulate more lipids than those from wild-type animals. Conversely, OGG1 overexpression significantly blunts adipogenic differentiation and lipid accretion in both pre-adipocytes from Ogg1Tg mice, as well as in 3T3-L1 cells with adenovirus-mediated OGG1 overexpression. Mechanistically, changes in adipogenesis are accompanied by significant alterations in cellular PARylation, corresponding with OGG1 genotype. Specifically, deletion of OGG1 reduces protein PARylation, concomitant with increased adipogenic differentiation, while OGG1 overexpression significantly increases PARylation and blunts adipogenesis. Collectively, these data indicate a novel role for OGG1 in modulating adipocyte differentiation and lipid accretion. These findings have important implications to our knowledge of the fundamental process of adipocyte differentiation, as well as to our understanding of lipid-related diseases such as obesity.
6. Frontiers in Cell and Developmental Biology, 2021 Sep;9: 718962.
Maternal Transmission of Human OGG1 Protects Mice Against Genetically- and Diet-Induced Obesity Through Increased Tissue Mitochondrial Content.
Natalie Burchat1, Priyanka Sharma1, Hong Ye1, Sai Santosh Babu Komakula1,2, Agnieszka Dobrzyn1,2, Vladimir Vartanian3, R. Stephen Lloyd3,4 and Harini Sampath1,5,6.
1. Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, United States
2. Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Warsaw, Poland
3. Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, OR, United States
4. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, United States
5. Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, United States
6. Center for Microbiome, Nutrition, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, United States
Obesity and related metabolic disorders are pressing public health concerns, raising the risk for a multitude of chronic diseases. Obesity is multi-factorial disease, with both diet and lifestyle, as well as genetic and developmental factors leading to alterations in energy balance. In this regard, a novel role for DNA repair glycosylases in modulating risk for obesity has been previously established. Global deletion of either of two different glycosylases with varying substrate specificities, Nei-like endonuclease 1 (NEIL1) or 8-oxoguanine DNA glycosylase-1 (OGG1), both predispose mice to diet-induced obesity (DIO). Conversely, enhanced expression of the human OGG1 gene renders mice resistant to obesity and adiposity. This resistance to DIO is mediated through increases in whole body energy expenditure and increased respiration in adipose tissue. Here, we report that hOGG1 expression also confers resistance to genetically-induced obesity. While Agouti obese (Ay/a) mice are hyperphagic and consequently develop obesity on a chow diet, hOGG1 expression in Ay/a mice (Ay/aTg) prevents increased body weight, without reducing food intake. Instead, obesity resistance in Ay/aTg mice is accompanied by increased whole body energy expenditure and tissue mitochondrial content. We also report for the first time that OGG1-mediated obesity resistance in both the Ay/a model and DIO model requires maternal transmission of the hOGG1 transgene. Maternal, but not paternal, transmission of the hOGG1 transgene is associated with obesity resistance and increased mitochondrial content in adipose tissue. These data demonstrate a critical role for OGG1 in modulating energy balance through changes in adipose tissue function. They also demonstrate the importance of OGG1 in modulating developmental programming of mitochondrial content and quality, thereby determining metabolic outcomes in offspring.
7. Nature, 28 April 2022; 604:714
Somatic genomic changes in single Alzheimer’s disease neurons.
Michael B. Miller1,2,3,4,14, August Yue Huang2,3,4,14, Junho Kim2,3,4,5, et al.
1. Division of Neuropathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
2. Division of Genetics and Genomics, Manton Center for Orphan Diseases, Boston Children’s Hospital, Boston, MA, USA.
3. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4. Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
5. Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea.
14. Department of Neurology, Harvard Medical School, Boston, MA, USA.
Dementia in Alzheimer’s disease progresses alongside neurodegeneration, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations at rates similar to those of dividing cells which suggests that genetic factors, environmental exposures or disease states might influence this accumulation. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer’s disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer’s disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely
resembles ‘clock-like’ mutational signatures that have been previously described in healthy and cancerous cells. In neurons affected by Alzheimer’s disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation, which we show is increased in Alzheimer’s-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer’s disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer’s disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer’s disease.