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MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis.

ABSTRACT: 8-Oxoguanine (8-oxoG), a major oxidative base lesion, is highly accumulated in Alzheimer's disease (AD) brains during the pathogenic process. MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby avoiding 8-oxo-dG incorporation into DNA. 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired with cytosine in DNA, thereby minimizing 8-oxoG accumulation in DNA. Levels of MTH1 and OGG1 are significantly reduced in the brains of sporadic AD cases. To understand how 8-oxoG accumulation in the genome is involved in AD pathogenesis, we established an AD mouse model with knockout of Mth1 and Ogg1 genes in a 3xTg-AD background. MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and, to a lesser extent, mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4-5 months of age. Furthermore, minocycline, which inhibits microglial activation and reduces neuroinflammation, markedly decreased the nuclear accumulation of 8-oxoG in microglia, and inhibited microgliosis and neuronal loss. Gene expression profiling revealed that MTH1 and OGG1 efficiently suppress progression of AD by inducing various protective genes against AD pathogenesis initiated by Aß/Tau accumulation in 3xTg-AD brain. Our findings indicate that efficient suppression of 8-oxoG accumulation in brain genomes is a new approach for prevention and treatment of AD.

SUBMITTER: Oka S

PROVIDER: S-EPMC7988129 | biostudies-literature |

REPOSITORIES: biostudies-literature

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MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis

Project description:To investigate the role of 8-oxo-7, 8-dihydroguanine (8-oxoguanine) accumulation in DNA or nucleotide pools during the development of AD pathology, we introduced a Mth1/Ogg1-double deficiency into homozygous triple-transgenic AD model (3xTg-AD-H) mice. Mth1 encodes 8-oxo-7, 8-dihydro-2'-deoxyguanosine-5'-triphosphatase (8-oxo-dGTPase) and Ogg1 encodes 8-oxoguanine DNA glycosylase 1. One-way eBays ANOVA of microarray data from hippocampi revealed that the gene expression profiles are most significantly altered in the hippocampi of 3xTg-AD-H with Mth1/Ogg1-double deficient (ADH/TO-DKH) mice compared to non-Tg control (NT) mice. Comparative analysis between 3xTg-AD-H (ADH/WT) and ADH/TO-DKH mice showed that the expression of genes involved in neuroprotection are significantly altered. Among them, expression of the AD-related genes including Ttr, Enpp2, Kcnj13 and Kl was significantly downregulated in ADH/TO-DKH mice.

2021-03-24 | GSE83996 | GEO

Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1).

Project description:The DNA base excision repair (BER) pathway, which utilizes DNA glycosylases to initiate repair of specific DNA lesions, is the major pathway for the repair of DNA damage induced by oxidation, alkylation, and deamination. Early results from clinical trials suggest that inhibiting certain enzymes in the BER pathway can be a useful anticancer strategy when combined with certain DNA-damaging agents or tumor-specific genetic deficiencies. Despite this general validation of BER enzymes as drug targets, there are many enzymes that function in the BER pathway that have few, if any, specific inhibitors. There is a growing body of evidence that suggests inhibition of 8-oxoguanine DNA glycosylase-1 (OGG1) could be useful as a monotherapy or in combination therapy to treat certain types of cancer. To identify inhibitors of OGG1, a fluorescence-based screen was developed to analyze OGG1 activity in a high-throughput manner. From a primary screen of ?50,000 molecules, 13 inhibitors were identified, 12 of which were hydrazides or acyl hydrazones. Five inhibitors with an IC50 value of less than 1 ?M were chosen for further experimentation and verified using two additional biochemical assays. None of the five OGG1 inhibitors reduced DNA binding of OGG1 to a 7,8-dihydro-8-oxoguanine (8-oxo-Gua)-containing substrate, but all five inhibited Schiff base formation during OGG1-mediated catalysis. All of these inhibitors displayed a >100-fold selectivity for OGG1 relative to several other DNA glycosylases involved in repair of oxidatively damaged bases. These inhibitors represent the most potent and selective OGG1 inhibitors identified to date.

| S-EPMC4894821 | biostudies-literature

Dual Inhibitors of 8-Oxoguanine Surveillance by OGG1 and NUDT1.

Project description:Oxidative damage in DNA is one of the primary sources of mutations in the cell. The activities of repair enzymes 8-oxoguanine DNA glycosylase (OGG1) and human MutT Homologue 1 (NUDT1 or MTH1), which work together to ameliorate this damage, are closely linked to mutagenesis, genotoxicity, cancer, and inflammation. Here we have undertaken the development of small-molecule dual inhibitors of the two enzymes as tools to test the relationships between these pathways and disease. The compounds preserve key structural elements of known inhibitors of the two enzymes, and they were synthesized and assayed with recently developed luminescence assays of the enzymes. Further structural refinement of initial lead molecules yielded compound 5 (SU0383) with IC50(NUDT1) = 0.034 μM and IC50(OGG1) = 0.49 μM. The compound SU0383 displayed low toxicity in two human cell lines at 10 μM. Experiments confirm the ability of SU0383 to increase sensitivity of tumor cells to oxidative stress. Dual inhibitors of these two enzymes are expected to be useful in testing multiple hypotheses regarding the roles of 8-oxo-dG in multiple disease states.

| S-EPMC7061906 | biostudies-literature

8-Oxoguanine DNA glycosylase (OGG1) deficiency increases susceptibility to obesity and metabolic dysfunction.

Project description:Oxidative damage to DNA is mainly repaired via base excision repair, a pathway that is catalyzed by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). While OGG1 has been implicated in maintaining genomic integrity and preventing tumorigenesis, we report a novel role for OGG1 in altering cellular and whole body energy homeostasis. OGG1-deficient (Ogg1(-/-)) mice have increased adiposity and hepatic steatosis following exposure to a high-fat diet (HFD), compared to wild-type (WT) animals. Ogg1(-/-) animals also have higher plasma insulin levels and impaired glucose tolerance upon HFD feeding, relative to WT counterparts. Analysis of energy expenditure revealed that HFD-fed Ogg1(-/-) mice have a higher resting VCO(2) and consequently, an increased respiratory quotient during the resting phase, indicating a preference for carbohydrate metabolism over fat oxidation in these mice. Additionally, microarray and quantitative PCR analyses revealed that key genes of fatty acid oxidation, including carnitine palmitoyl transferase-1, and the integral transcriptional co-activator Pgc-1? were significantly downregulated in Ogg1(-/-) livers. Multiple genes involved in TCA cycle metabolism were also significantly reduced in livers of Ogg1(-/-) mice. Furthermore, hepatic glycogen stores were diminished, and fasting plasma ketones were significantly reduced in Ogg1(-/-) mice. Collectively, these data indicate that OGG1 deficiency alters cellular substrate metabolism, favoring a fat sparing phenotype, that results in increased susceptibility to obesity and related pathologies in Ogg1(-/-) mice.

| S-EPMC3524114 | biostudies-literature

An active alternative splicing isoform of human mitochondrial 8-oxoguanine DNA glycosylase (OGG1).

Project description:Eight alternatively spliced isoforms of human 8-oxoguanine DNA glycosylase (OGG1) (OGG1-1a, -1b, -1c, -2a, -2b, -2c, -2d and -2e) are registered at the National Center for Biotechnology Information (NCBI). OGG1-1a is present in the nucleus, whereas the other seven isoforms are present in the mitochondria. Recombinant OGG1-1a has been purified and enzyme kinetics determined. OGG1(s) in mitochondria have not been fully characterized biochemically until recently. The major mitochondrial OGG1 isoform, OGG1-2a (also named β-OGG1), has also been expressed and purified; however, its activity is unresolved. Recently, we purified recombinant mitochondrial OGG1-1b and found that it was an active OGG1 enzyme. We reported its enzyme kinetics and compared the results with those of OGG1-1a. The reaction rate constant of OGG1-1b 8-oxoG glycosylase activity (k g) was 8-oxoG:C > > 8-oxoG:T > > 8-oxoG:G > 8-oxoG:A and was similar to that of OGG1-1a under single-turnover conditions ([E] > [S]). Both OGG1-1b and OGG1-1a showed high specificity towards 8-oxoG:C. The reaction rate constant of OGG1-1b N-glycosylase/DNA lyase activity (k gl) was 8-oxoG:C > 8-oxoG:T ≃ 8-oxoG:G > > 8-oxoG:A and that of OGG1-1a was 8-oxoG:C > 8-oxoG:T, 8-oxoG:G and 8-oxoG:A. The k gl of OGG1-1b and OGG1-1a is one order of magnitude lower than the corresponding k g value. OGG1-1b showed an especially low k gl towards 8-oxoG:A. Comparable expression of OGG1-1a and OGG1-1b was detected by RT-PCR in normal human lung tissue and lung cell lines. These results suggest that OGG1-1b is associated with 8-oxoG cleavage in human lung mitochondria and that the mechanism of this repair is similar to that of nuclear OGG1-1a. Currently, the other five mitochondrial OGG1 isoforms have not been isolated. I summarize information on OGG1 isoform mRNAs, coding DNA sequences and amino acid sequences that are archived by the National Center for Biotechnology Information.

| S-EPMC4917946 | biostudies-literature

Poly(ADP-ribose) polymerase 1 (PARP-1) binds to 8-oxoguanine-DNA glycosylase (OGG1).

Project description:Human 8-oxoguanine-DNA glycosylase (OGG1) plays a major role in the base excision repair pathway by removing 8-oxoguanine base lesions generated by reactive oxygen species. Here we report a novel interaction between OGG1 and Poly(ADP-ribose) polymerase 1 (PARP-1), a DNA-damage sensor protein involved in DNA repair and many other cellular processes. We found that OGG1 binds directly to PARP-1 through the N-terminal region of OGG1, and this interaction is enhanced by oxidative stress. Furthermore, OGG1 binds to PARP-1 through its BRCA1 C-terminal (BRCT) domain. OGG1 stimulated the poly(ADP-ribosyl)ation activity of PARP-1, whereas decreased poly(ADP-ribose) levels were observed in OGG1(-/-) cells compared with wild-type cells in response to DNA damage. Importantly, activated PARP-1 inhibits OGG1. Although the OGG1 polymorphic variant proteins R229Q and S326C bind to PARP-1, these proteins were defective in activating PARP-1. Furthermore, OGG1(-/-) cells were more sensitive to PARP inhibitors alone or in combination with a DNA-damaging agent. These findings indicate that OGG1 binding to PARP-1 plays a functional role in the repair of oxidative DNA damage.

| S-EPMC3247967 | biostudies-literature

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

Project description: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.

| S-EPMC5519207 | biostudies-literature

PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase.

Project description:Telomerase counteracts telomere shortening and cellular senescence in germ, stem, and cancer cells by adding repetitive DNA sequences to the ends of chromosomes. Telomeres are susceptible to damage by reactive oxygen species (ROS), but the consequences of oxidation of telomeres on telomere length and the mechanisms that protect from ROS-mediated telomere damage are not well understood. In particular, 8-oxoguanine nucleotides at 3' ends of telomeric substrates inhibit telomerase in vitro, whereas, at internal positions, they suppress G-quadruplex formation and were therefore proposed to promote telomerase activity. Here, we disrupt the peroxiredoxin 1 (PRDX1) and 7,8-dihydro-8-oxoguanine triphosphatase (MTH1) genes in cancer cells and demonstrate that PRDX1 and MTH1 cooperate to prevent accumulation of oxidized guanine in the genome. Concomitant disruption of PRDX1 and MTH1 leads to ROS concentration-dependent continuous shortening of telomeres, which is due to efficient inhibition of telomere extension by telomerase. Our results identify antioxidant systems that are required to protect telomeres from oxidation and are necessary to allow telomere maintenance by telomerase conferring immortality to cancer cells.

| S-EPMC6004070 | biostudies-literature

O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts.

Project description:mtDNA damage in cardiac myocytes resulting from increased oxidative stress is emerging as an important factor in the pathogenesis of diabetic cardiomyopathy. A prevalent lesion that occurs in mtDNA damage is the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), which can cause mutations when not repaired properly by 8-oxoguanine DNA glycosylase (Ogg1). Although the mtDNA repair machinery has been described in cardiac myocytes, the regulation of this repair has been incompletely investigated. Here we report that the hearts of type 1 diabetic mice, despite having increased Ogg1 protein levels, had significantly lower Ogg1 activity than the hearts of control, non-type 1 diabetic mice. In diabetic hearts, we further observed increased levels of 8-OHdG and an increased amount of mtDNA damage. Interestingly, Ogg1 was found to be highly O-GlcNAcylated in diabetic mice compared with controls. In vitro experiments demonstrated that O-GlcNAcylation inhibits Ogg1 activity, which could explain the mtDNA lesion accumulation observed in vivo Reducing Ogg1 O-GlcNAcylation in vivo by introducing a dominant negative O-GlcNAc transferase mutant (F460A) restored Ogg1 enzymatic activity and, consequently, reduced 8-OHdG and mtDNA damage despite the adverse hyperglycemic milieu. Taken together, our results implicate hyperglycemia-induced O-GlcNAcylation of Ogg1 in increased mtDNA damage and, therefore, provide a new plausible biochemical mechanism for diabetic cardiomyopathy.

| S-EPMC5159511 | biostudies-literature

Effect of 8-oxoguanine DNA glycosylase 1 (OGG1) inhibitor on pro-inflammatory gene expression.

Project description:Balbc J mouse received vehicle (solvent) or OGG1 inhibitor 1 h prior to treatment via intraperitoneal route. Tumor necrosis factor alpha (TNFa, 20 ng per ml) was installed into lungs via intranasal route in 60 microliters of solvent). One hour after TNFa challenge mice were sacrificed, lungs were removed and RNAs were isolated from individual lungs (n=6) After reverse transcription cDNAs were pooled and changes in gene expression was determined by using SABiosciences Mouse Inflammatory Cytokines & Receptors PCR Array (PAMM-011Z)

2018-07-10 | GSE116809 | GEO

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