Product inhibition and magnesium modulate the dual reaction mode of hOgg1

Morland, Ingrid; Luna, Luisa; Gustad, Ellen; Seeberg, Erling; Bjørås, Magnar

doi:10.1016/j.dnarep.2004.11.002

Cited by 43 publications

(41 citation statements)

References 37 publications

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“…By increasing the lyase activity through the targeting of recombinant hOGG1 to mitochondria, the buildup of this toxic intermediate can be blocked. It has recently been reported that the lyase activity of hOGG1 can be inhibited by high Mg 2ϩ concentrations (43). Although this effect may have important consequences on the action of this enzyme in the nucleus, we feel that the effects of Mg 2ϩ will be minimal in the matrix of mitochondria.…”

Section: Hogg1 Protects From Ffa-induced Apoptosismentioning

confidence: 65%

Protection of INS-1 Cells From Free Fatty Acid–Induced Apoptosis by Targeting hOGG1 to Mitochondria

et al. 2006

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Chronic exposure to elevated levels of free fatty acids (FFAs) impairs pancreatic ␤-cell function and contributes to the decline of insulin secretion in type 2 diabetes. Previously, we reported that FFAs caused increased nitric oxide (NO) production, which damaged mitochondrial DNA (mtDNA) and ultimately led to apoptosis in INS-1 cells. To firmly establish the link between FFA-generated mtDNA damage and apoptosis, we stably transfected INS-1 cells with an expression vector containing the gene for the DNA repair enzyme human 8-oxoguanine DNA glycosylase/ apurinic lyase (hOGG1) downstream of the mitochondrial targeting sequence (MTS) from manganese superoxide dismutase. Successful integration of MTS-OGG1 into the INS-1 cellular genome was confirmed by Southern blot analysis. Western blots and enzyme activity assays revealed that hOGG1 was targeted to mitochondria and the recombinant enzyme was active. MTS-OGG1 cells showed a significant decrease in FFA-induced mtDNA damage compared with vector-only transfectants. Additionally, hOGG1 overexpression in mitochondria decreased FFA-induced inhibition of ATP production and protected INS-1 cells from apoptosis. These results indicate that mtDNA damage plays a pivotal role in FFA-induced ␤-cell dysfunction and apoptosis. Therefore, targeting DNA repair enzymes into ␤-cell mitochondria could be a potential therapeutic strategy for preventing or delaying the onset of type 2 diabetes symptoms. Diabetes 55:1022-1028, 2006 C hronic elevation of cellular free fatty acids (FFAs) is associated with both insulin resistance and type 2 diabetes (1,2). Results obtained from a variety of different laboratories suggest that the accumulation of lipid into islet tissue is deleterious to normal ␤-cell function and that this elevation in FFA content ultimately leads to ␤-cell failure and death through a process termed "lipotoxicity." Exposure of ␤-cells to high concentrations of FFAs has been correlated with impaired insulin secretion and changes in the expression of genes involved in the lipogenic and fat oxidation pathways and is considered to be an important factor in the pathogenesis of type 2 diabetes (3,4). Moreover, FFAs have been shown to cause ␤-cell death by both apoptotic and necrotic mechanisms (5,6). Although the exact mechanisms involved in FFA-induced apoptosis and necrosis remain to be clarified, it has been suggested that the ␤-cell dysfunction and death observed in type 2 diabetes may involve exaggerated activation of the inducible form of nitric oxide synthase (iNOS) by FFAs with the consequent generation of excess nitric oxide (NO) (7).Although NO plays a prominent role in regulating many biological functions, a growing body of evidence indicates that at high concentrations, it can also be cytotoxic and mutagenic (8). However, the cellular targets with which NO interacts have not been fully identified. We hypothesized that one of these targets might be mitochondrial DNA (mtDNA). Recently, we reported that FFAs (2:1, oleate:palmitate) caused a rise in NO production that ...

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Section: Hogg1 Protects From Ffa-induced Apoptosismentioning

confidence: 65%

Protection of INS-1 Cells From Free Fatty Acid–Induced Apoptosis by Targeting hOGG1 to Mitochondria

et al. 2006

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“…The Schiff base formation between hOGG1-and 8-oxoG-containing DNA was abrogated in the presence of Mg 2ϩ . These results suggest that hOGG1 operates mainly as a monofunctional glycosylase under physiologic concentrations of Mg 2ϩ (22). There…”

mentioning

confidence: 71%

“…It is reported that 5-10% of total Mg 2ϩ is in a free state in the cells (21). A recent report suggests that Mg 2ϩ reduces the efficiency of the base excision and strand incision activities of hOGG1 on DNA containing 8-oxoG under single turnover conditions (22); however, the reduction was more pronounced for the AP-lyase activity. The Schiff base formation between hOGG1-and 8-oxoG-containing DNA was abrogated in the presence of Mg .…”

mentioning

confidence: 99%

Magnesium, Essential for Base Excision Repair Enzymes, Inhibits Substrate Binding of N-Methylpurine-DNA Glycosylase

Adhikari

Toretsky

Yuan

et al. 2006

Journal of Biological Chemistry

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is an absolute requirement for the downstream activities of the major base excision repair enzymes, it may act as a regulator for the base excision repair pathway for efficient and balanced repair of damaged bases, which are often less toxic and/or mutagenic than their subsequent repair product intermediates.Cellular DNA is continuously exposed to endogenous or exogenous chemical or physical agents that induce DNA lesions. DNA base damage threatens genomic stability and cellular viability. Multiple DNA repair pathways exist in all organisms, from bacteria to humans, to preserve the integrity of the genome (1). If not repaired, damaged bases could be mutagenic (2) and/or cause cell death by blocking DNA replication (3).In all organisms, repair of DNA-containing small adducts, as well as altered and abnormal bases, occurs primarily via the base excision repair (BER) 2 pathway, beginning with cleavage of the base by a DNA glycosylase (1, 2). Mechanistically, DNA glycosylases are categorized into two classes: mono-and bifunctional DNA glycosylases. Monofunctional DNA glycosylases, such as N-methylpurine-DNA glycosylase (MPG) and uracil-DNA glycosylase, use an activated water molecule as a nucleophile to generate an apurinic or apyrimidinic (AP) site in DNA. Bifunctional DNA glycosylases/AP lyases, such as NTH1 and OGG1, use an activated amino group (Lys) or imino group (Pro) as the nucleophile to create a Schiff base intermediate that coordinates base removal and subsequent strand incision (AP lyase) 3Ј to the AP site (4, 5). The mammalian MPG is known to excise at least 17 structurally diverse modified bases from DNA (6). These lesions include 3-alkylpurines, 7-alkylguanine, 1,N 6 -ethenoadenine (⑀A), N 2 ,3-ethenoguanine, and hypoxanthine (Hx), all of which are purine derivatives (7-12). Moreover, the base alterations are located in both the major and minor grooves of duplex DNA. Its orthologs in Escherichia coli (AlkA) and yeast (MAG) have an overlapping although not identical substrate range. Nonetheless mammalian MPG and E. coli AlkA do not share significant sequence similarity or structural homology (13,14), despite this functional similarity and the fact that 3-methyladenine is a preferred substrate for both. MPG excises ⑀A and Hx more efficiently than AlkA and MAG (11), but unlike AlkA, it cannot excise O 2 -alkylpyrimidines (15, 16) and oxidized bases such as 5-formyluracil and 5-hydroxymethyluracil (17) (22); however, the reduction was more pronounced for the AP-lyase activity. The Schiff base formation between hOGG1-and 8-oxoG-containing DNA was abrogated in the presence of Mg 2ϩ . These results suggest that hOGG1 operates mainly as a monofunctional glycosylase under physiologic concentrations of Mg 2ϩ (22). There

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“…Although it possesses two activities, previous work suggested that the AP lyase activity of OGG1 is not essential and that OGG1 may act as a monofunctional glycosylase in vivo (13,14). The OGG1 knock-out mouse exhibits greater levels of genomic 8-oxoG and also shows an increase in G:C to T:A transversions in genomic DNA that is correlated with a predisposition to tumorigenesis (15)(16)(17).…”

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confidence: 99%

DNA Sequence Context Effects on the Glycosylase Activity of Human 8-Oxoguanine DNA Glycosylase

Sassa

Beard

Prasad

et al. 2012

Journal of Biological Chemistry

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Background: Human 8-oxoguanine DNA glycosylase (OGG1) removes the mutagenic DNA lesion 7,8-dihydro-8-oxoguanine. Results: OGG1 activity is significantly decreased by an adjacent DNA mismatch. Conclusion: Tandem lesions can dramatically diminish base excision repair. Significance: Deamination of 5Ј-methylcytosine in CpG-rich DNA sequences prone to oxidative DNA damage could be a significant factor in the generation of G to T transversions hot spots.

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Product inhibition and magnesium modulate the dual reaction mode of hOgg1

Cited by 43 publications

References 37 publications

Protection of INS-1 Cells From Free Fatty Acid–Induced Apoptosis by Targeting hOGG1 to Mitochondria

Protection of INS-1 Cells From Free Fatty Acid–Induced Apoptosis by Targeting hOGG1 to Mitochondria

Magnesium, Essential for Base Excision Repair Enzymes, Inhibits Substrate Binding of N-Methylpurine-DNA Glycosylase

DNA Sequence Context Effects on the Glycosylase Activity of Human 8-Oxoguanine DNA Glycosylase

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