Disease relevance of OGG1

• One class utilizes an internal Lys residue as the active site nucleophile, and includes Escherichia coli Nth and both known mammalian DNA glycosylase/AP lyases, namely, OGG1 and NTH1 [1].
• RESULTS: Polymorphism OGG1 S326C was associated with an increased risk of colorectal cancer [odds ratio (OR), 2.3; 95% confidence interval (95% CI), 1.1-5.0], the risk being higher in younger individuals [2].
• They found increased lung cancer risk among subjects carrying the OGG1 Cys/Cys genotype (odds ratio (OR) = 1.24, 95% confidence interval (CI): 1.01, 1.53), using 3,253 cases and 3,371 controls from seven studies; this is consistent with experimental evidence that this isoform exhibits decreased activity [3].
• Nonetheless, published data were consistent with associations between: (a) the OGG1 S326C variant and increased risk of various types of cancer; (b) the XRCC1 R194W variant and reduced risk of various types of cancer; and (c) the BRCA2 N372H variant and increased risk of breast cancer [4].
• In contrast, significant association was not observed for the GSTM1, CYP1A1, and OGG1 polymorphisms with lung adenocarcinoma risk, although several studies have shown their implication in the risk for squamous cell lung carcinoma [5].
• A greater proportion of the hOGG1-over-expressing hepatoma cells experienced apoptosis [6].

Psychiatry related information on OGG1

• Expression of 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer's disease brain [7].
• Of the known isoforms of the hOGG1 enzyme (types Ia, Ib, Ic, Id, and II), only 1, Ia, is found in the nucleus, whereas the rest show a mitochondrial distribution [8].
• Despite the large individual differences among the six subjects measured, data suggest that a single-bout of aerobic exercise increases the activity of hOGG1 which is responsible for the excision of 8-oxoG [9].

High impact information on OGG1

• The structure reveals the mechanistic basis for the recognition and catalytic excision of DNA damage by hOGG1 and by other members of the enzyme superfamily to which it belongs [10].
• The dedicated repair pathway for oxoG centres on 8-oxoguanine DNA glycosylase (hOGG1), an enzyme that recognizes oxoG x C base pairs, catalysing expulsion of the oxoG and cleavage of the DNA backbone [10].
• Here we report the X-ray structure of the catalytic core of hOGG1 bound to oxoG x C-containing DNA at 2.1 A resolution [10].
• This library was found to contain a cDNA structurally and functionally related to genes in bacteria and yeast for the DNA repair enzyme 8-oxoguanine DNA glycosylase [11].
• Augmented expression of a human gene for 8-oxoguanine DNA glycosylase (MutM) in B lymphocytes of the dark zone in lymph node germinal centers [11].

Chemical compound and disease context of OGG1

• For the detection and measurement of oxidative clustered DNA lesions, we used adaptations of number average length analysis, constant-field agarose gel electrophoresis, putrescine, and the repair enzymes APE1, OGG1 (human) and Nth1 (E. coli) [12].
• To assess the role of 8-oxoguanine glycosylase (OGG1) in the cell defense against radiation injury, the radiation-induced cytotoxicities were compared between the mutant type KG-1 featuring a loss of OGG1 activity due to a homozygous mutation of Arg 229 Gln, and the wild type U937 [13].
• These findings suggest that OGG1 plays an important role in cell survival from radiation-induced damage and are also indicative of the capability of 8-hydroxyguanine in DNA to induce cellular toxicities [13].
• Lack of the DNA repair enzyme OGG1 sensitizes dopamine neurons to manganese toxicity during development [14].
• To investigate potential non-receptor-mediated estrogen effects, we evaluated the association between COMT Val158Met and hOGG1 Ser326Cys polymorphisms and prostate cancer in a family-based case-control study (439 prostate cancer cases, 479 brother controls) [15].

Biological context of OGG1

• We demonstrate that XPC-HR23B complex acts as cofactor in base excision repair of 8-OH-Gua, by stimulating the activity of its specific DNA glycosylase OGG1 [16].
• Consistent with these results, deletion of both OGG1 encoding 8oxoG-DNA glycosylase and APN1 causes nearly 46-fold synergistic increase in the spontaneous mutation rate, and this enhanced mutagenesis is primarily due to G . C to T . A transversions [17].
• The enhanced rate of repair of 8-oxoG in the genome by wild-type OGG1 but not the K338R/K341R mutant, ectopically expressed in oxidatively stressed OGG1-null mouse embryonic fibroblasts, suggests that acetylation increases OGG1 activity in vivo [18].
• Based on these results, we propose a novel regulatory function of OGG1 acetylation in repair of its substrates in oxidatively stressed cells [18].
• There is a great deal of interest in the up- or down-regulation of OGG1 expression after DNA damage [19].

Anatomical context of OGG1

• About 20% of OGG1 is present in acetylated form in HeLa cells [18].
• For the OGG1 polymorphism, the repair of 8-oxo-guainine from DNA was measured in three panel cell lines that differed in their OGG1 genotype [20].
• 8-oxoguanine DNA glycosylase (OGG1) DNA repair activity was measured, as incision activity of a lymphocyte extract on DNA containing the OGG1 substrate 8-oxoguanine [21].
• 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 [22].
• 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 [22].

Associations of OGG1 with chemical compounds

• Western blotting and semiquantitative reverse transcription-PCR revealed that cadmium treatment caused a decrease in the expression level of human OGG1 (8-oxoguanine-DNA glycosylase-1; hOGG1) in human fibroblast GM00637 and HeLa S3 cells [23].
• Transcription factors NF-YA regulate the induction of human OGG1 following DNA-alkylating agent methylmethane sulfonate (MMS) treatment [19].
• This novel collaboration of two DNA glycosylases, which do not stably interact with each other, in stimulating 8-oxoguanine repair is possible because of higher AP site affinity and stronger AP lyase activity of NEIL1 relative to OGG1 [24].
• Suppressive activities of OGG1 and MYH proteins against G:C to T:A mutations caused by 8-hydroxyguanine but not by benzo[a]pyrene diol epoxide in human cells in vivo [25].
• Sodium dichromate at 25 microM and above gave a marked reduction of OGG1 mRNA expression which was not seen at 1 microM and below [26].

Physical interactions of OGG1

• The altered substrate specificity, lack of stimulation by AP-endonuclease 1 (APE1) and anomalous DNA binding conformation of S326C OGG1 may contribute to its linkage to cancer incidence [27].
• Here, we report that XRCC1 interacts physically and functionally with hOGG1, the human DNA glycosylase that initiates the repair by BER of the mutagenic oxidized base 8-oxoguanine [28].
• In addition, the cadmium-mediated decrease in hOGG1 transcription was the result of decreased binding of the transcription factor Sp1 to the hOGG1 promoter [23].
• Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter [29].

Enzymatic interactions of OGG1

• 8-Oxoguanine (8-oxoG), a major ROS product in the genome, is excised by 8-oxoG-DNA glycosylase (OGG1) and the resulting abasic (AP) site is cleaved by AP-endonuclease (APE1) in the initial steps of repair [30].

Regulatory relationships of OGG1

• The glycosylase activity of S326C OGG1 was not significantly stimulated by the presence of AP-endonuclease [27].
• XRCC1 stimulates the formation of the hOGG1 Schiff-base DNA intermediate without interfering with the endonuclease activity of APE1, the second enzyme in the pathway [28].
• Functional analysis showed that p53 significantly enhanced the sequential activities of hOGG1 and APE in excising the 8-oxoG nucleotide from DNA in vitro [31].
• Using an 8-oxoguanine DNA glycosylase (OGG1)-specific siRNAs, we also found that MT-III expression resulted in the suppression of the gamma-radiation-induced 8-oxoG accumulation and mutation in the OGG1-depleted cells [32].
• Furthermore, evidence is presented to support the hypothesis that wild type CSB regulates expression of OGG1 [33].

Other interactions of OGG1

• Based on these observations, we further characterized expression and intracellular localization of 8-oxoG DNA glycosylase (hOGG1) and 2-OH-A/adenine DNA glycosylase (hMYH) in human cells [34].
• Proteins related to DNA damage and repair, such as Ku, poly(ADP-ribosyl) polymerase, OGG1, and MSH2 were selectively up-regulated in malgun cells [35].
• The mRNA levels of the nucleotide excision DNA repair gene ERCC1 and the base excision DNA repair gene OGG1 were quantified in 43 healthy volunteers in a dietary intervention trial as markers for the DNA repair capacity [36].
• Stimulation of DNA glycosylase activity of OGG1 by NEIL1: functional collaboration between two human DNA glycosylases [24].
• Using multifactor dimensionality reduction approach, the four-factor model, including smoking status, OGG1 S326C (rs1052133), APEX1 D148E (rs3136820), and ADPRT762 (rs1136410), had the best ability to predict bladder cancer risk with the highest cross-validation consistency (100%) and the lowest prediction error (37.02%; P < 0.001) [37].

Analytical, diagnostic and therapeutic context of OGG1

• Treatment with sodium dichromate (0-100 microM, 16 h) resulted in a concentration-dependent decrease in the levels of OGG1 mRNA as measured by both RT-PCR and RNase protection assay [26].
• Case-control studies of genetic polymorphisms in DNA repair enzymes suggest that the common variant Ser326Cys in OGG1 may be a risk factor for lung cancer, whereas a rare variant in OGG1 and germ line mutations in the corresponding mismatch repair gene MYH are risk factors for hereditary colon cancer [38].
• We found that the upstream AP-4 site within the OGG1 promoter is responsible and that Tat interacted with AP-4 and removed AP-4 from the OGG1 promoter by in vivo chromatin immunoprecipitation assay [39].
• Measurement of oxidative damage at individual gene levels by quantitative PCR using 8-hydroxyguanine glycosylase (OGG1) [40].
• By radiation hybrid panel mapping, OGG1 was localized between WI-4179 and AFMA216ZG1 at 3p26, proximal to the VHL gene [41].

References