Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:6.5.1.2 (DNA ligase)
2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

8-oxoguanine DNA glycosylase (OGG1), a major DNA repair enzyme in mammalian cells and a component of the base excision repair (BER) pathway, was recently shown to be associated with the microtubule network and the centriole at interphase and the spindle assembly at mitosis. In this study, we determined whether other participants in the BER pathway also bind microtubules in situ and in vitro. Purified recombinant human DNA polymerase beta (DNA Pol beta) and purified recombinant mNEIL2 were chemically conjugated to fluorochromes and photosensitive dyes and used in in situ localization and binding experiments. Results from in situ localization, microtubule co-precipitation and site-directed photochemical experiments showed that recombinant human DNA Pol beta and recombinant mNEIL2 associated with microtubules in situ and in vitro in a manner similar to that shown earlier for another BER pathway component, OGG1. Observations reported in this study suggest that these BER pathway components are microtubule-associated proteins (MAPs) themselves or utilize yet to be identified MAPs to bind microtubules in order to regulate their intracellular trafficking and activities during the cell cycle.
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PMID:The murine DNA glycosylase NEIL2 (mNEIL2) and human DNA polymerase beta bind microtubules in situ and in vitro. 1572 23

Nitric oxide (NO) that is produced by inducible NO synthase (iNOS) in glial cells is thought to contribute significantly to the pathogenesis of multiple sclerosis. Oligodendrocytes can be stimulated to express iNOS by inflammatory cytokines, which are known to accumulate in the multiple sclerotic brain. The potentially pathological levels of NO produced under these circumstances can target a wide spectrum of intracellular components. We hypothesized that one of the critical targets for damage that leads to disease is mtDNA. In this study, we found that cytokines, in particular a combination of tumor necrosis factor-alpha (50 ng/ml) and IFNgamma (25 ng/ml), cause elevated NO production in primary cultures of rat oligodendrocytes. Western blot analysis revealed a strong enhancement of iNOS expression 48 h after cytokine treatment. Within the same time period, NO-mediated mtDNA damage was shown by Southern blot analysis and by ligation-mediated PCR. Targeting the DNA repair enzyme human 8-oxoguanine DNA glycosylase (hOGG1) to the mitochondria of oligodendrocytes had a protective effect against this cytokine-mediated mtDNA damage. Moreover, it was shown that mitochondrial transport sequence hOGG1-transfected oligodendrocytes had fewer apoptotic cells compared with cells containing vector only following treatment with the cytokines. Subsequent experiments revealed that targeting hOGG1 to mitochondria reduces the activation of caspase-9, showing that this recombinant protein works to reduce apoptosis that is occurring through a mitochondria-based pathway.
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PMID:Cytokines induce nitric oxide-mediated mtDNA damage and apoptosis in oligodendrocytes. Protective role of targeting 8-oxoguanine glycosylase to mitochondria. 1581 55

We have tested the hypothesis that training with moderate- (MT), strenuous- (ST), or over- (OT) load can cause alterations in memory, lipid peroxidation, protein oxidation, DNA damage, activity of 8-oxoG-DNA glycosylase (OGG1) and brain-derived neurotrophic factor (BDNF), in rat brain. Rat memory was assessed by a passive avoidance test and the ST and OT group demonstrated improved memory. The content of BDNF was increased only in the OT group. The oxidative damage of lipids and DNA, as measured by thiobarbituric acid reactive substances (TBARS), and 8-hydroxydeoxyguanosine (8-OHdG), did not change significantly with exercise. Similarly, the activity of DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), was not altered with exercise training. On the other hand, the content of reactive carbonyl derivatives (RCDs) decreased in all groups and the decrease reached significance levels in the ST and OT groups. The activity of the proteasome complex increased in the brain of OT. The findings of this study imply that over-training does not induce oxidative stress in the brain and does not cause loss of memory. The improved memory was associated with enhanced BDNF content.
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PMID:The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain. 1586 41

The human homologue of the yeast DNA repair enzyme 8-oxoguanine DNA glycosylase (hOGG1) repairs oxidatively damaged guanosine nucleotides in DNA. This enzyme is highly expressed in reactive germinal centers, where lymphoid cells are under oxidative stress, and has been thought to protect lymphocytes from mutation. As a first step to investigate the role of hOGG1 in lymphomagenesis, we evaluated hOGG1 expression in follicular lymphoma. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue of 28 follicular lymphoma cases (16 grade 1, seven grade 2, and five grade 3) to evaluate the expression of hOGG1 in neoplastic follicles. Reactive germinal centers of non-neoplastic tonsil and lymph node tissue were also examined. Fluorescent-in-situ hybridization (FISH) was performed using a DNA probe from BAC clone RP11-266J6 corresponding to 3p25, where the hOGG1 gene resides, to evaluate for the presence or absence of a deletion. In reactive germinal centers, the majority of centroblasts and centrocytes were positive for hOGG1. In contrast, the majority (21 of 28 or 75%) of follicular lymphoma cases showed absent/minimal expression of hOGG1. Only four of 28 (14%) follicular lymphoma cases revealed the same levels of hOGG1 expression as reactive germinal centers. There was no correlation between hOGG1 expression and histologic grade. None of the 16 cases evaluated by FISH showed a deletion of hOGG1. Furthermore, absent/minimal hOGG1 expression was observed in four of six Bcl-2-negative follicular lymphoma cases. Our findings suggest that absent/minimal hOGG1 expression occurs in the majority of follicular lymphomas. The downregulation of hOGG1 does not appear to be due to a deletion of the hOGG1 locus. Additionally, finding absent/minimal hOGG1 expression in a subset of Bcl-2-negative follicular lymphomas suggests that hOGG1 may have utility in diagnosing Bcl-2-negative follicular lymphomas.
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PMID:Expression of human 8-oxoguanine DNA glycosylase (hOGG1) in follicular lymphoma. 1605 51

8-oxoguanine DNA glycosylase and Kin17 are proteins widely distributed and phylogenetically conserved in the CNS. 8-oxoguanine DNA glycosylase is a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine present in DNA damaged by oxidative stress. Kin17 protein is involved in DNA repair and illegitimate recombination in eukaryotic cells. The present study evaluates the effect of ovarian hormones on the expression of both proteins in the magnocellular paraventricular nucleus of the hypothalamus and the bed nucleus of the stria terminalis in female and male rat brains. In the paraventricular nucleus, ovariectomy induced a significant decrease in the number of 8-oxoguanine DNA glycosylase-positive nuclei as well as in their relative fluorescent intensity as compared with ovariectomized-estradiol treated and proestrous groups. Confocal microscopy observation demonstrated that oxoguanine DNA glycosylase protein is located in the Hoechst-dyed nuclei and cytoplasm in male and ovariectomized rats. Surprisingly, following estradiol administration to ovariectomized and proestrous rats, the 8-oxoguanine DNA glycosylase immunolabeling was observed in the nucleolus, the cytoplasm and the dendrites of cells, while Kin17 protein was always localized in the cell nuclei. In the bed nucleus of the stria terminalis, the number of 8-oxoguanine DNA glycosylase-positive nuclei during proestrous was significantly lower than the number obtained in males and ovariectomized rats and similar to the number of ovariectomized-estradiol-treated groups. In contrast to these observations, no significant differences were observed in the expression of kin17 protein. Our results suggest that estrogens differentially regulate the expression of 8-oxoguanine DNA glycosylase, but not that of Kin17 protein, in specific regions of the rat brain and that estradiol can translocate the 8-oxoguanine DNA glycosylase protein within nuclei and to other subcellular compartments.
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PMID:8-oxoguanine DNA glycosylase, but not Kin17 protein, is translocated and differentially regulated by estrogens in rat brain cells. 1618 50

Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead (Pb) has been shown to elevate the Alzheimer's disease (AD) related beta-amyloid peptide (Abeta), which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine (oxo8dG) levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase (Ogg1) in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life (Postnatal day 5), but was later elevated 20 months after exposure to Pb had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase (SOD1), manganese-SOD (SOD2), and reduced-form glutathion (GSH). These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances.
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PMID:Exposure to lead and the developmental origin of oxidative DNA damage in the aging brain. 1648 31

Chronic exposure to elevated levels of free fatty acids (FFAs) impairs pancreatic beta-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 beta-cell dysfunction and apoptosis. Therefore, targeting DNA repair enzymes into beta-cell mitochondria could be a potential therapeutic strategy for preventing or delaying the onset of type 2 diabetes symptoms.
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PMID:Protection of INS-1 cells from free fatty acid-induced apoptosis by targeting hOGG1 to mitochondria. 1656 24

DNA-damaging agents usually produce a vast collection of lesions within the genome. Analysis of these lesions from the structural and biological viewpoints is often complicated by the reality that some of the lesions are chemically fragile, leading to an even larger set of secondary and tertiary products. In an effort to deconvolute complex DNA-damage spectra, a strategy is presented whereby an oligonucleotide containing a specific target for chemical reaction is allowed to react with a DNA-damaging agent. A large collection of HPLC-resolvable modified oligonucleotides is generated, and chromatographically distinct members of the set are then individually characterized using chemical, spectroscopic, biochemical, and genetic probes. The biological component of this "chemical-biological fingerprinting" tool is the use of polymerase bypass in vivo in cells having defined replication status and quantitative and qualitative patterns of lesion-directed mutagenesis, as key properties that complement physical analysis of modified DNA. This approach was applied to the complex product spectrum generated by peroxynitrite in the presence of CO2; peroxynitrite is a powerful oxidizing and nitrating agent generated as part of immune response. An oligonucleotide containing the primary oxidation product, 7,8-dihydro-8-oxoguanine (8-oxoGua), which is highly susceptible to further oxidation and/or nitration, was treated with peroxynitrite. Using mass spectrometry, coelution with authentic standards, sensitivity to piperidine, recognition and strand cleavage by the DNA repair enzyme MutM, and mutagenicity and genotoxicity in vivo, a matrix was created that defined the properties of the secondary DNA lesions formed when 3-morpholinosydnonimine (SIN-1) delivered a low, constant flux of peroxynitrite to an oligonucleotide containing 8-oxoGua. Two lesions were identified as the diastereomers of spiroiminodihydantoin (Sp), which had been observed previously in nucleoside-based experiments employing SIN-1. A third lesion, triazine, was tentatively identified. However, in addition to these lesions, a number of secondary lesions were generated that had chemical-biological fingerprints inconsistent with that of any known 8-oxoGua-derived lesion described to date. In vitro experiments showed that while some of these newly characterized secondary lesions were removed from DNA by MutM, others were in fact very poor substrates for this repair enzyme. These 8-oxoGua-derived lesions also showed varying degrees of sensitivity to piperidine. Furthermore, all of the secondary lesions observed in this work were potently mutagenic and genotoxic in Escherichia coli. Therefore, while 8-oxoGua itself is nontoxic and only mildly mutagenic in repair-proficient cells, peroxynitrite reveals the promutagenic potential and triggers the covert nature of this DNA lesion.
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PMID:Chemical-biological fingerprinting: probing the properties of DNA lesions formed by peroxynitrite. 1794 98

Leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a surrogate marker of oxidant-induced DNA damage in patients undergoing maintenance hemodialysis (MHD). Glutathione S-transferase M1 (GST M1) is a member of the GST family of proteins, which protect cellular DNA against oxidative damage. This study tested the association of a common GST M1 gene polymorphism [GST M1(-)], known to produce a dysfunctional enzyme, with levels of 8-OHdG in peripheral blood leukocytes and all-cause mortality among MHD patients. Among 488 MHD patients and 372 gender-matched healthy subjects, the frequency of the GST M1(-) genotype was 63.1 and 60.2%, respectively. The GST M1(-) genotype was associated with significantly higher levels of leukocyte 8-OHdG compared with the GST M1(+) genotype, even after adjustment for potential confounders (P < 0.001). Moreover, GST M1(-) patients who also had a common polymorphism in the DNA repair enzyme 8-oxoguanine DNA glycosylase 1 or who underwent dialysis with a bioincompatible cellulose membrane had the highest median levels of leukocyte 8-OHdG. Multivariate Cox regression revealed that among MHD patients, GST M1(-) genotype approximately doubled the risk for all-cause mortality (hazard ratio 2.24; 95% confidence interval 1.30 to 4.51) during the mean follow-up of 34 mo. In conclusion, patients without GST M1 activity are more vulnerable to oxidative stress and are at greater risk for death compared with those who possess GST M1 activity.
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PMID:GST M1 polymorphism associates with DNA oxidative damage and mortality among hemodialysis patients. 1905 70

To observe the alteration in the expression of DNA repair enzymes hOGG1 and hMYHalpha and the change in 8-OHdG levels in the HBx gene-transfected cells HepG2/HBx and to explore the mechanisms of the HBV-associated hepatocellular carcinoma, the gene-transfected cells HepG2/HBx which stably expressed HBx was established, and the effect of HBx on the cell cycle and proliferation of HepG2 was examined. By using the beta-actin as the interior control, real-time polymerase chain reaction (Real-time qPCR) was employed to quantitatively detect the expression of DNA repair enzymes hOGG1 and hMYHalpha in the HepG2/HBx, the control cells HepG2 and HepG2 transfected with pcDNA3.1 vector (HepG2/pDNA3.1). The 8-OHdG levels were determined by HPLC/ECD in the established gene-transfected cells HepG2/HBx and the control cells HepG2 and HepG2/pcDNA3.1. Our results showed that the expression of DNA repair enzyme hMYHalpha in the HepG2/HBx (0.021+/-0.007) was significantly lower than that of HepG2 (0.099+/-0.041) (P<0.05) and HepG2/pDNA3.1 (0.121+/-0.005) (P<0.05). However, the no significant differences existed in the expression of DNA repair enzyme hOGG1 among the three cell strains (P>0.05). The 8-OHdG level in the HepG2/HBx was significantly higher than that in HepG2 and HepG2/pcDNA3.1 (P<0.05). It is concluded that HBx gene may inhibit the expression of DNA repair enzyme hMYHalpha mRNA to impair the ability to repair the intracellular DNA oxidative damage, to increase the oxidative DNA-adduct 8-OHdG and to affect the nucleotide excision repair function, thus participate in the occurrence and development of hepatocellular carcinoma.
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PMID:The effects of HBx gene on the expression of DNA repair enzymes hOGG1 and hMYHalpha mRNA in HepG2 cells. 1939 2


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