DNA repair gene 8-oxoguanine DNA glycosylase Ser326Cys polymorphism and colorectal cancer risk in a Kashmiri population

8-Oxoguanine DNA glycosylase (OGG1) is one of the important base excision repair enzymes that repair 8-oxoguanine lesion incorporated within the DNA of an individual by reactive oxygen species. The aim of this study was to detect the role of OGG1 Ser326Cys polymorphism in susceptibility to colorectal cancer (CRC) in a Kashmiri population. We investigated the genotype distribution of the OGG1 gene in 114 CRC cases in comparison with 200 healthy subjects. There was no significant association between OGG1 Ser326Cys polymorphism and CRC, but the homozygous Cys/Cys variant genotype was associated with an increased risk of colon cancer (p<0.05). This study suggests that the OGG1 polymorphism is not associated with the risk of development of CRC in the Kashmiri population in general but modulates the risk of cancer development in colon via interaction with many dietary factors.     

Effects of physical exercise training in DNA damage and repair activity in humans with different genetic polymorphisms of hOGG1 (Ser326Cys)

The main purpose of this pilot study was to investigate the possible influence of genetic polymorphisms of the hOGG1 (Ser326Cys) gene in DNA damage and repair activity by 8‐oxoguanine DNA glycosylase 1 (OGG1 enzyme) in response to 16 weeks of combined physical exercise training. Thirty‐two healthy Caucasian men (40–74 years old) were enrolled in this study. All the subjects were submitted to a training of 16 weeks of combined physical exercise. The subjects with Ser/Ser genotype were considered as wild‐type group (WTG), and Ser/Cys and Cys/Cys genotype were analysed together as mutant group (MG). We used comet assay in conjunction with formamidopyrimidine DNA glycoslyase (FPG) to analyse both strand breaks and FPG‐sensitive sites. DNA repair activity were also analysed with the comet assay technique. Our results showed no differences between DNA damage (both strand breaks and FPG‐sensitive sites) and repair activity (OGG1) between genotype groups (in the pre‐training condition). Regarding the possible influence of genotype in the response to 16 weeks of physical exercise training, the results revealed a decrease in DNA strand breaks in both groups, a decrease in FPG‐sensitive sites and an increase in total antioxidant capacity in the WTG, but no changes were found in MG. No significant changes in DNA repair activity was observed in both genotype groups with physical exercise training. This preliminary study suggests the possibility of different responses in DNA damage to the physical exercise training, considering the hOGG1 Ser326Cys polymorphism. Copyright © 2015 John Wiley & Sons, Ltd.     

Interactions between the OGG1 Ser326Cys polymorphism and intake of fruit and vegetables in relation to lung cancer

The enzyme 8-oxoguanine glycosylase 1 (OGG1) repairs oxidatively damaged DNA and a polymorphism in the OGG1 gene (Ser³²⁶Cys) has been associated with lung cancer. We examined associations between the polymorphism and intake of fruits and vegetables and smoking in the development of lung cancer, by genotyping blood samples from 431 lung cancer cases and 796 comparison persons, which were identified within a prospective cohort on 57,000 cohort members. We found no overall association between the OGG1 polymorphism and lung cancer. There was a statistically significant interaction between the polymorphism and dietary intake of vegetables, with a 54% decrease in lung cancer risk per 50% increase in vegetable intake among homozygous Cys³²⁶Cys carriers and no decrease in risk among carriers of Ser³²⁶Ser or Ser³²⁶Cys. The same tendency was seen in relation to intake of fruit. There were no statistically significant interactions between the OGG1 polymorphism and smoking.     

OGG1 expression and OGG1 Ser326Cys polymorphism and risk of lung cancer in a prospective study

Oxidative DNA damage is believed to be implicated in lung carcinogenesis. 8-OxodG is a mutagenic and abundant oxidative modification induced in DNA. OGG1, NEIL1 and MUTYH are all involved in the repair and prevention of 8-oxodG-derived mutations and may be up-regulated by oxidative stress. The polymorphism OGG1 Ser326Cys has in some studies been associated with risk of lung cancer. In a population-based cohort of 57,053 Danes, we examined associations between mRNA levels of OGG1, NEIL1, MUTYH and NUDT in buffy coat material and subsequent lung cancer risk. 260 cases with lung cancer were identified and a sub-cohort of 263 individuals was matched on sex, age and smoking duration. We found that OGG1 mRNA levels in healthy individuals were not associated with risk of subsequent getting lung cancer. However, subjects with the OGG1 Cys326/Cys326 genotype had a higher expression level of OGG1 mRNA than wildtype-allele carriers. For homozygous Cys326 carriers, the incidence rate ratio (IRR) was 1.51 (95% CI: 1.09-2.08) for a doubling of the OGG1 mRNA level and there was a statistically significant interaction between the genotype and mRNA level. Among never-smokers, the IRR was 4.29 (1.09-16.9) per doubling of the OGG1 mRNA level, which was not found among smokers. Furthermore, we found a positive correlation between OGG1 mRNA expression and urinary excretion of 8-oxodG (RS=0.18; p<0.005). NUDT1 mRNA levels were omitted due to low and unreliable expression levels. The results suggest that OGG1 mRNA levels should be regarded as a biomarker of exposure to oxidative stress with induction of DNA rather than a marker of inborn DNA repair capacity.     

Association between DNA damage, DNA repair genes variability and clinical characteristics in breast cancer patients

The cell's susceptibility to DNA damage and its ability to repair this damage are important for cancer induction, promotion and progression. In the present work we determined the level of basal (total endogenous) and endogenous oxidative DNA damage as well as polymorphism of the DNA repair genes: RAD51 (135 G/C), XRCC3 (Thr241Met), OGG1 (Ser326Cys) and XPD (Lys751Gln) in peripheral blood lymphocytes of 41 breast cancer patients and 48 healthy individuals. DNA damage was evaluated by alkaline comet assay with DNA repair enzymes: Endo III and Fpg, preferentially recognizing oxidized DNA bases. The genotypes of the polymorphisms were determined by restriction fragment length polymorphism PCR. We observed a strong association between breast cancer occurrence and the genotypes C/C of the RAD51-135G/C polymorphism, Ser/Ser of the OGG1-Ser326Cys and Lys/Gln of the XPD-Lys751Gln, whereas the genotypes G/C of the RAD51-135G/C and Lys/Lys of the XPD-Lys751Gln exerted a protective effect against breast cancer. We also found that individuals with the G/C genotype of the RAD51-135G/C polymorphism and with the Lys/Lys genotype of the XPD-Lys751Gln polymorphism displayed a lower extent of basal and oxidative DNA damage. A strong association between higher level of oxidative DNA damage and the Lys/Gln genotype of the latter polymorphism was found. We also correlated genotypes with clinical characteristics of breast cancer patients. We observed a strong association between the G/C genotype of the RAD51-135 G/C polymorphism and the expression of the progesterone receptor and between both alleles of the OGG1-Ser326Cys polymorphism and lymph node metastasis. Our results suggest that the polymorphism of the RAD51, OGG1 and XPD genes may be linked with breast cancer by the modulation of the cellular response to oxidative stress and these polymorphisms may be considered as markers in breast cancer along with the genetic or/and environmental indicators of oxidative stress.     

Direct visualization of repair of oxidative damage by OGG1 in the nuclei of live cells

Oxidative DNA damage caused by intracellular reactive oxygen species (ROS) is widely considered to be important in the pathology of a range of human diseases including cancer as well as in the aging process. A frequently occurring mutagenic base lesion produced by ROS is 8-oxo deoxyguanine (8-oxo dG) and the major enzyme for repair of 8-oxo dG is 8-oxoguanine-DNA glycosylase 1 (OGG1). There is now substantial evidence from bulk biochemical studies that a common human polymorphic variant of OGG1 (Ser326Cys) is repair deficient, and this has been linked to individual risk of pathologies related to oxidative stress. In the current study, we have used the technique of multiphoton microscopy to induce highly localized oxidative DNA damage in discrete regions of the nucleus of live cells. Cells transfected with GFP-tagged OGG1 proteins demonstrated rapid (<2 min) accumulation of OGG1 at sites of laser-induced damage as indicated by accumulation of GFP-fluorescence. This was followed by repair as evidenced by loss of the localized fluorescence over time. Quantification of the rate of repair confirmed that the Cys326 variant of OGG1 is repair deficient and that the initial repair rate of damage by Cys326 OGG1 was 3 to 4 fold slower than that observed for Ser326 OGG1. These values are in good agreement with kinetic data comparing the Ser326 and Cys326 proteins obtained by biochemical studies.     

The role of GSTM1, GSTT1, GSTP1, and OGG1 polymorphisms in type 2 diabetes mellitus risk: a case-control study in a Turkish population

The aim of the present study was to investigate the role of some polymorphisms in GSTs (GSTM1, GSTT1 and GSTP1) which are very important protective mechanisms against oxidative stress and in OGG1 gene which is important in DNA repair, against the risk of type 2 diabetes mellitus (T2DM). 127 T2DM and 127 control subjects were included in the study. DNA was extracted from whole blood. Analyses of GSTM1 and GSTT1 gene polymorphisms were performed by allele specific PCR and those of GSTP1 Ile105Val and OGG1 Ser326Cys by PCR-RFLP. Our data showed that GSTM1 null genotype frequency had a 2-6 times statistically significant increase in a patient group (OR=3.841, 95% CI=2.280-6.469, p<0.001) but no significance with GSTT1 null/positive and GSTP1 Ile105Val genotypes was observed. When T2DM patients with OGG1 Ser326Cys polymorphism were compared with patients with a wild genotype, a 2-3 times statistically significant increase has been observed (OR 1.858, 95% CI=1.099-3.141, p=0.021). The combined effect of GSTM1 null and OGG1 variant genotype frequencies has shown to be statistically significant. Similarly, the risk of T2DM was statistically increased with GSTM1 null (OR=3.841, 95% CI=2.28-6.469), GSTT1 null+GSTP1 (H+M) (OR=4.118, 95% CI=1.327-12.778) and GSTM1 null+OGG1 (H+M) (OR=3.322, 95% CI=1.898-5.816) and GSTT1 null+OGG1 (H+M) (OR=2.179, 95% CI=1.083-4.386) as compared to the control group. According to our study results, it has been observed that the combined evaluation of GSTM1-GSTT1-GSTP1 and OGG1 Ser326Cys gene polymorphisms can be used as candidate genes in the etiology of T2DM, especially in the development of T2DM.     

Cellular accumulation of Cys326-OGG1 protein complexes under conditions of oxidative stress

The common Ser326Cys polymorphism in the base excision repair protein 8-oxoguanine glycosylase 1 is associated with a reduced capacity to repair oxidative DNA damage particularly under conditions of intracellular oxidative stress and there is evidence that Cys326-OGG1 homozygous individuals have increased susceptibility to specific cancer types. Indirect biochemical studies have shown that reduced repair capacity is related to OGG1 redox modification and also possibly OGG1 dimer formation. In the current study we have used bimolecular fluorescence complementation to study for the first time a component of the base excision repair pathway and applied it to visualise accumulation of Cys326-OGG1 protein complexes in the native cellular environment. Fluorescence was observed both within and around the cell nucleus, was shown to be specific to cells expressing Cys326-OGG1 and only occurred in cells under conditions of cellular oxidative stress following depletion of intracellular glutathione levels by treatment with buthionine sulphoximine. Furthermore, OGG1 complex formation was inhibited by incubation of cells with the thiol reducing agents β-mercaptoethanol and dithiothreitol and the antioxidant dimethylsulfoxide indicating a causative role for oxidative stress in the formation of OGG1 cellular complexes.     

Activity of OGG1 variants in the repair of pro-oxidant-induced 8-oxo-2'-deoxyguanosine

Cells are continuously exposed to damaging reactive oxygen species (ROS), which are produced from both endogenous and exogenous sources. 8-Oxodeoxyguanosine (8-oxodG) is an abundant base lesion formed during oxidative stress which, if not repaired, can give rise to G:C-->T:A transversions in DNA. The 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated base excision repair (BER) pathway operates to remove 8-oxodG lesions. Ogg1 deletion and polymorphism may result in a hypermutator phenotype and susceptibility to oxidative pathologies including cancer. Limited and conflicting evidence exists regarding the repair capacity of a prevalent human OGG1 (hOGG1) polymorphism, the Cys326-hOGG1 variant. The formamidopyrimidine DNA glycosylase (FPG)-modified comet assay was used to investigate the ability of sodium dichromate, potassium bromate and Ro19-8022 (+light) to induce DNA damage in mogg1(-/-) null (KO) and wild-type (WT) mouse embryonic fibroblasts (MEFs) and to assess hOGG1 variant-initiated BER capacities under conditions of oxidative stress. Treatment of WT MEFs with these pro-oxidant agents induced direct DNA strand breaks in a concentration-dependent manner, whereas, identical treatment of KO MEFs produced no effect. In contrast, KO MEFs accumulated significantly more FPG-sensitive sites than WT MEFs. Expression of hOGG1 in KO MEFs restored the WT phenotype in response to all pro-oxidants tested. The results suggest OGG1-initiated BER generates direct DNA strand breaks detected by the conventional comet assay, thus it is important that researchers do not interpret these as direct damage per se but rather a reflection of the repair process. The data also indicate Cys326-hOGG1-initiated BER is transiently impaired with respect to Ser326-hOGG1 (wild-type)- and Gly326-hOGG1 (artificial)-initiated BER following pro-oxidant treatment, possibly via hOGG1 cysteine 326 oxidation. This finding suggests the homozygous cys326/cys326 genotype may be classified as a biomarker of disease susceptibility, which is in support of a growing body of epidemiological evidence.     

Role of OGG1 Ser326Cys polymorphism and 8-oxoguanine DNA damage in risk assessment of squamous cell carcinoma of head and neck in North Indian population

Squamous cell carcinoma of head and neck (SCCHN), one of the leading cancers worldwide, is most prevalent in Indian sub-continent. The major risk factors involved are smoking and consumption of alcohol, since they provide high free radical generating environment. We studied 8-oxoguanine DNA-glycosylase (OGG1) Ser326Cys polymorphism in 278 SCCHN cases and 278 matched controls by PCR-RFLP and observed that the variant genotype Ser/Cys exhibited an enhanced risk of ～1.7 folds (OR=1.71, 95% CI=1.20-2.93) and Cys/Cys ～2.5 folds (OR=2.55, 95% CI=1.29-5.00). Furthermore, we found a significant increase in salivary cell 8-OHdG with respect to Ser/Cys and Cys/Cys genotypes of OGG1 in SCCHN cases, when compared to Ser/Ser and Ser/Cys genotypes of the control population. Our results demonstrate that Ser326Cys variant genotype is associated with an increased risk of SCCHN in north India. Ser326Cys variant genotype was found to accumulate more of 8-OHdG, which may serve as a biomarker for early diagnosis of SCCHN.     

SNPs in DNA repair genes associated to meningitis and host immune response

In vitro and in animal models, APE1, OGG1, and PARP-1 have been proposed as being involved with inflammatory response. In this work, we have investigated if the SNPs APE1 Asn148Glu, OGG1 Ser326Cys, and PARP-1 Val762Ala are associated to meningitis. The patient genotypes were investigated by PIRA-PCR or PCR-RFLP. DNA damages were detected in genomic DNA by Fpg treatment. IgG and IgA were measured from plasma and the cytokines and chemokines were measured from cerebrospinal fluid samples using Bio-Plex assays. A higher frequency (P<0.05) of APE1 Glu allele in bacterial meningitis (BM) and aseptic meningitis (AM) patients was observed. The genotypes Asn/Asn in control group and Asn/Glu in BM group was also higher. For the SNP OGG1 Ser326Cys, the genotype Cys/Cys was more frequent (P<0.05) in BM group. The frequency of PARP-1 Val/Val genotype was higher in control group (P<0.05). The occurrence of combined SNPs is significantly higher in BM patients, indicating that these SNPs may be associated to the disease. Increasing in sensitive sites to Fpg was observed in carriers of APE1 Glu allele or OGG1 Cys allele, suggesting that SNPs affect DNA repair activity. Alterations in IgG production were observed in the presence of SNPs APE1 Asn148Glu, OGG1 Ser326Cys or PARP-1 Val762Ala. Moreover, reduction in the levels of IL-6, IL-1Ra, MCP-1/CCL2 and IL-8/CXCL8 was observed in the presence of APE1 Glu allele in BM patients. In conclusion, we obtained indications of an effect of SNPs in DNA repair genes on the regulation of immune response in meningitis.     

Chronic exposure to sublethal doses of radiation mimetic Zeocin selects for clones deficient in homologous recombination

Research indicates that exposure to hypoxia is associated with oxidative stress. In this investigation, healthy subjects were exposed to hypoxia by inhalation of 10% oxygen for 2 h (corresponding to 5500 m above sea level). The levels of strand breaks and oxidatively damaged purine bases, measured by the comet assay, and the expression of genes involved in DNA repair of oxidatively damaged DNA were investigated in mononuclear blood cells (MNBC) at baseline, after 2 h of hypoxia, 2 h of reoxygenation, and 1 day and 8 days after the exposure. The level of strand breaks and oxidized purine bases in MNBC increased following both the 2 h of hypoxia and the 2 h reoxygenation period, whereas this effect was not observed in unexposed subjects. The expressions of oxoguanine DNA glycosylase 1 (OGG1), nucleoside diphosphate linked moiety X-type motif 1 (NUDT1), nei endonuclease VIII-like 1 (NEIL1), and mutY homolog (MUTYH) were unaltered throughout the experiment in both groups of subjects, indicating that DNA repair genes are not up-regulated by the hypoxia and reoxygenation treatment. Taken together, this report shows that inhalation of 10% oxygen for 2 h is associated with increased number of oxidized DNA lesions in MNBC, but acute hypoxia may not inflict upon the regulation of genes involved in repair of oxidized DNA.     

The 8-oxoguanine DNA N-glycosylase 1 (hOGG1) Ser326Cys variant affects the susceptibility to Graves' disease

Oxidative DNA damage, caused by either endogenous or exogenous sources of reactive oxygen species (ROS), has been linked several diseases including Graves' disease (GD). 7,8‐Dihydro‐8‐oxoguanine (8‐oxoG) is a major lesion produced by ROS and is considered a key biomarker of oxidative DNA damage. In humans, 8‐oxoG is mainly repaired by 8‐oxoguanine DNA N‐glycosylase‐1 (hOGG1), which is an essential component of the base excision repair (BER) pathway. The functional studies showed that hOGG1 Ser326Cys polymorphism is associated with the reduced DNA repair activity and increased risk for some oxidative stress‐related diseases. In this study, we firstly investigated hOGG1 Ser326Cys polymorphism in GD. According to our results, Cys/Cys genotype frequency in the GD patients (23.4%) was significantly higher than the controls (9.2%). Cys/Cys genotype had an 3.5‐fold [95% CI (confidence interval): 2.10–6.01, p < 0.001] the Cys allele had 1.83‐fold (95% CI: 1.43–2.34, p < 0.001) increase in the risk for developing GD. Our results suggest that Ser326Cys polymorphism of the hOGG1 gene is associated with GD risk. Copyright © 2011 John Wiley & Sons, Ltd.     

Dimerization and opposite base-dependent catalytic impairment of polymorphic S326C OGG1 glycosylase

Human 8-oxoguanine-DNA glycosylase (OGG1) is the major enzyme for repairing 8-oxoguanine (8-oxoG), a mutagenic guanine base lesion produced by reactive oxygen species (ROS). A frequently occurring OGG1 polymorphism in human populations results in the substitution of serine 326 for cysteine (S326C). The 326 C/C genotype is linked to numerous cancers, although the mechanism of carcinogenesis associated with the variant is unclear. We performed detailed enzymatic studies of polymorphic OGG1 and found functional defects in the enzyme. S326C OGG1 excised 8-oxoG from duplex DNA and cleaved abasic sites at rates 2- to 6-fold lower than the wild-type enzyme, depending upon the base opposite the lesion. Binding experiments showed that the polymorphic OGG1 binds DNA damage with significantly less affinity than the wild-type enzyme. Remarkably, gel shift, chemical cross-linking and gel filtration experiments showed that S326C both exists in solution and binds damaged DNA as a dimer. S326C OGG1 enzyme expressed in human cells was also found to have reduced activity and a dimeric conformation. The glycosylase activity of S326C OGG1 was not significantly stimulated by the presence of AP-endonuclease. 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.     

Association between 8-oxo-7,8-dihydroguanine excretion and risk of lung cancer in a prospective study

Oxidative damage to guanine (8-oxoGua) is one of the most abundant lesions induced by oxidative stress and documented mutagenic. 8-Oxoguanine DNA glycosylase 1 (OGG1) removes 8-oxoGua from DNA by excision. The urinary excretion of 8-oxoGua is a biomarker of exposure, reflecting the rate of damage in the steady state. The aim of this study was to investigate urinary 8-oxoGua as a risk factor for lung cancer. In a nested case-cohort design we examined associations between urinary excretion of 8-oxoGua and risk of lung cancer as well as potential interaction with the OGG1 Ser326Cys polymorphism in a population-based cohort of 25,717 men and 27,972 women aged 50-64 years with 3-7 years follow-up. We included 260 cases with lung cancer and a subcohort of 263 individuals matched on sex, age, and smoking duration for comparison. Urine collected at entry was analysed for 8-oxoGua by HPLC with electrochemical detection. There was no significant effect of smoking or OGG1 genotype on the excretion of 8-oxoGua. Overall the incidence rate ratio (IRR) (95% confidence interval) of lung cancer was 1.06 (0.97-1.15) per doubling of 8-oxoGua excretion. The association between lung cancer risk and 8-oxoGua excretion was significant among men [IRR: 1.17 (1.03-1.31)], never-smokers [IRR: 9.94 (1.04-94.7)], and former smokers [IRR: 1.19 (1.07-1.33)]. There was no significant interaction with the OGG1 genotype, although the IRR was 1.14 (0.98-1.34) among subjects homozygous for Cys326. The association between urinary 8-oxoGua excretion and lung cancer risk among former and never-smokers suggests that oxidative stress with damage to DNA is important in this group.     

XRCC1 Arg399Gln was associated with repair capacity for DNA damage induced by occupational chromium exposure

ABSTRACT: BACKGROUND: Occupational chromium exposure may induce DNA damage and lead to lung cancer and other work-related diseases. DNA repair gene polymorphisms, which may alter the efficiency of DNA repair, thus may contribute to genetic susceptibility of DNA damage. The aim of this study was to test the hypothesis that the genetic variations of 9 major DNA repair genes could modulate the hexavalent chromium (Cr (VI))-induced DNA damage. FINDINGS: The median (P25-P75) of Olive tail moment was 0.93 (0.58-1.79) for individuals carrying GG genotype of XRCC1 Arg399Gln (G/A), 0.73 (0.46-1.35) for GA heterozygote and 0.50 (0.43-0.93) for AA genotype. Significant difference was found among the subjects with three different genotypes (P = 0.048) after adjusting the confounding factors. The median of Olive tail moment of the subjects carrying A allele (the genotypes of AA and GA) was 0.66 (0.44-1.31), which was significantly lower than that of subjects with GG genotype (P = 0.043). The A allele conferred a significantly reduced risk of DNA damage with the OR of 0.39 (95% CI: 0.15-0.99, P = 0.048). No significant association was found between the XRCC1Arg194Trp, ERCC1 C8092A, ERCC5 His1104Asp, ERCC6 Gly399Asp, GSTP1 Ile105Val, OGG1 Ser326Cys, XPC Lys939Gln, XPD Lys751Gln and DNA damage. CONCLUSION: The polymorphism of Arg399Gln in XRCC1 was associated with the Cr (VI)- induced DNA damage. XRCC1 Arg399Gln may serve as a genetic biomarker of susceptibility for Cr (VI)- induced DNA damage.     

Are genetic polymorphisms in OGG1, XRCC1 and XRCC3 genes predictive for the DNA strand break repair phenotype and genotoxicity in workers exposed to low dose ionising radiations?

Identification of higher risk individuals carrying genetic polymorphisms responsible for reduced DNA repair capacity has substantial preventive implications as these individuals could be targeted for cancer prevention. We have conducted a study to assess the predictivity of the OGG1, XRCC1 and XRCC3 genotypes and the in vitro single strand break repair phenotype for the induction of genotoxic effects. At the population level, a significant contribution of the OGG1 genotypes to the in vitro DNA strand break repair capacity was found. At an individual level, the OGG1 variants Ser/Cys and Cys/Cys genotypes showed a slower in vitro DNA repair than the Ser/Ser OGG1genotype. A multivariate analysis performed with genotypes, age, cumulative dose, exposure status and smoking as independent variables indicated that in the control population, repair capacity is influenced by age and OGG1 polymorphisms. In the exposed population, DNA damage is greater in older men and in smokers. Repair capacity is slower in individuals with Ser/Cys or Cys/Cys OGG1 genotypes compared to those with the Ser/Ser OGG1 genotype. Micronuclei (MN) frequencies increased with age and the cumulative dose of gamma-rays. Analysis of the total population revealed that genetic polymorphisms in XRCC1 resulted in higher residual DNA (RDNA) values and the Met/Met variant of XRCC3 resulted in an increased frequency of micronuclei. The analysis confirms that MN frequencies are reliable biomarkers for the assessment of genetic effects in workers exposed to ionising radiation (IR). A combined analysis of the three genotypes, OGG1, XRCC1 and XRCC3 polymorphisms is advised in order to assess individual susceptibility to ionising radiation. As an alternative or complement, the in vitro DNA strand break repair phenotype which integrates several repair pathways is recommended. Smokers with OGG1 polymorphisms who are exposed to ionising radiation represent a specific population requiring closer medical surveillance because of their increased mutagenic/carcinogenic risk.     

hOGG1 Ser326Cys polymorphism and renal cell carcinoma risk in a Chinese population

Oxidative DNA damage caused by reactive oxygen species plays an important role in cancer development. Human 8-oxoguanine DNA glycosylase (hOGG1) is involved in base excision repair of 8-oxoguanine from damaged DNA. We hypothesized that variants in the hOGG1 gene are associated with risk of renal cell carcinoma (RCC). In a hospital-based case-control study of 572 RCC patients and 575 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism Ser326Cys (rs1052133) and assessed its associations with risk of RCC in a Chinese population. We found that individuals with the Cys allele were associated with an increased risk of RCC (odds ratio [OR]?=?1.40, 95% confidence interval [CI]?=?1.02-1.90), compared with those with the Ser/Ser genotype, particularly among subgroups of body mass index >24?kg/m(2) (OR?=?1.75, 95% CI?=?1.12-2.73) and non-smokers (OR?=?1.60, 95% CI?=?1.07-2.38). Further, the polymorphism was associated with risk of developing localized stage and well-differentiated RCC. Our results suggested that the polymorphism is involved in the etiology of RCC and thus may be a marker for genetic susceptibility to RCC.     

PARP-1 Expression is Increased in Colon Adenoma and Carcinoma and Correlates with OGG1

The ethiology of colon cancer is largely dependent on inflammation driven oxidative stress. The analysis of 8-oxodeoxyguanosine (8-oxodGuo) level in leukocyte DNA of healthy controls (138 individuals), patients with benign adenomas (AD, 137 individuals) and with malignant carcinomas (CRC, 169 individuals) revealed a significant increase in the level of 8-oxodGuo in leukocyte DNA of AD and CRC patients in comparison to controls. The counteracting mechanism is base excision repair, in which OGG1 and PARP-1 play a key role. We investigated the level of PARP-1 and OGG1 mRNA and protein in diseased and marginal, normal tissues taken from AD and CRC patients and in leukocytes taken from the patients as well as from healthy subjects. In colon tumors the PARP-1 mRNA level was higher than in unaffected colon tissue and in polyp tissues. A high positive correlation was found between PARP-1 and OGG1 mRNA levels in all investigated tissues. This suggests reciprocal influence of PARP-1 and OGG1 on their expression and stability, and may contribute to progression of colon cancer. PARP-1 and OGG1 proteins level was several fold higher in polyps and CRC in comparison to normal colon tissues. Individuals bearing the Cys326Cys genotype of OGG1 were characterized by higher PARP-1 protein level in diseased tissues than the Ser326Cys and Ser326Ser genotypes. Aforementioned result may suggest that the diseased cells with polymorphic OGG1 recruit more PARP protein, which is necessary to remove 8-oxodGuo. Thus, patients with decreased activity of OGG1/polymorphism of the OGG1 gene and higher 8-oxodGuo level may be more susceptible to treatment with PARP-1 inhibitors.