Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

8-Hydroxyguanine (8-OHG) is an oxidatively damaged mutagenic base which causes G:C-->T:A transversions in DNA. OGG1 was cloned as a human gene encoding a DNA glycosylase that specifically excises 8-OHG from DNA in vitro. However, it was not clear whether OGG1 protein suppresses G:C-->T:A transversions caused by 8-OHG in human cells in vivo. In the present study we have examined the ability of OGG1 protein to suppress G:C-->T:A transversions caused by 8-OHG in human cells by bacterial suppressor tRNA (supF) forward mutation assay using a shuttle vector DNA, pMY189. Introduction of a single 8-OHG residue at position 159 of the supF gene in plasmid pMY189 resulted in a 130-fold increase in mutation frequency compared with untreated plasmid pMY189 after replication in the NCI-H1299 human lung cancer cell line. G:C-->T:A transversions at position 159 were detected in >90% of the supF mutants from the 8-OHG-containing plasmid. The mutation frequency of the 8-OHG-containing plasmid was significantly reduced by overexpression of OGG1 protein in NCI-H1299 cells and, in particular, the occurrence of G:C-->T:A transversion at position 159 in the supF gene was suppressed. Furthermore, frequencies and spectra of mutations of the untreated pMY189 plasmid did not differ significantly with overexpression of OGG1 protein. These results indicate that OGG1 protein has the ability to suppress G:C-->T:A transversions caused by 8-OHG in human cells in vivo.
Carcinogenesis 2001 Sep
PMID:OGG1 protein suppresses G:C-->T:A mutation in a shuttle vector containing 8-hydroxyguanine in human cells. 1153 55

8-Hydroxyguanine (oh8G) is a major base lesion produced by reactive oxygen species. oh8G in DNA causes G:C to T:A transversions and, thus, could be responsible for mutations that lead to carcinogenesis. A human DNA glycosylase/AP lyase encoded by the OGG1 gene has an activity to remove directly oh8G from DNA, and suppresses the mutagenic effect of oh8G. OGG1 protein has a helix-hairpin-helix-GPD motif as a domain for both DNA binding and catalysis, a nuclear localization signal, and a mitochondria targeting signal. Among multiple OGG1 isoforms, OGG1-type la is expressed predominantly in human cells and repairs chromosomal DNA in the nucleus. Inactivation of the OGG1 gene in yeast and mice leads to elevated spontaneous mutation frequency in the cells. The human OGG1 gene maps to chromosome 3p26.2, and allelic deletions of this region occur frequently in a variety of human cancers. Moreover, the OGG1 gene is somatically mutated in some cancer cells and is highly polymorphic among human populations. Repair activities of some mutated and polymorphic OGG1 proteins are lower than those of wild-type OGG1-type la-Ser326 protein and, thus, could be involved in human carcinogenesis.
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PMID:The OGG1 gene encodes a repair enzyme for oxidatively damaged DNA and is involved in human carcinogenesis. 1155 47

Hexavalent chromium is a genotoxic human pulmonary carcinogen that elevates DNA oxidation, apparently through the generation of reactive DNA-damaging intermediates including Cr(V), Cr(IV) and reactive oxygen species. We tested the hypothesis that elevation of DNA oxidation may also be through inhibition of the expression of the repair glycosylase for 8-oxo deoxyguanine (hOGG1) in cultured A549 human lung epithelial cells. 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. Sodium dichromate at 25 microM and above gave a marked reduction of OGG1 mRNA expression which was not seen at 1 microM and below. No effect on the expression of the apurinic endonuclease hAPE or the house-keeping gene GAPDH was observed at any of the concentrations of sodium dichromate investigated. Treatment of cells with the pro-oxidant H(2)O(2) (0-200 microM) for 16 h had no detectable effect on the levels of OGG1 mRNA or protein expression suggesting that the effect of sodium dichromate is not mediated by H(2)O(2). Western blotting demonstrated that sodium dichromate (100 microM; 16 h and >25 microM; 28 h) markedly reduced levels of OGG1 protein in nuclear cell extracts. Additionally, treatment of cells with sodium dichromate (>25 microM, 28 h) resulted in a concentration-dependent decrease in the ability of nuclear extracts to nick a synthetic oligonucleotide containing 8-oxo deoxyguanine (8-oxo dG). We conclude that the elevation of 8-oxo dG levels observed in A549 cells treated with sodium dichromate may be, at least in part, due to a reduced capacity to repair endogenous and hexavalent chromium-induced 8-oxo dG.
Carcinogenesis 2002 Jan
PMID:Down-regulation of the DNA-repair endonuclease 8-oxo-guanine DNA glycosylase 1 (hOGG1) by sodium dichromate in cultured human A549 lung carcinoma cells. 1175 23

The human OGG1 (hOGG1) gene encodes a DNA glycosylase that is involved in the excision repair of 8-hydroxy-2'-deoxyguanine (8-OH-dG) from oxidatively-damaged DNA. To determine whether hOGG1 plays a role in risk for orolaryngeal cancer, we screened normal orolaryngeal tissue specimens for hOGG1 expression and assessed the role of the hOGG1 Ser326Cys polymorphism in risk for orolaryngeal cancer. hOGG1 expression was determined by reverse transcription-polymerase chain reaction of total RNA from aerodigestive tract tissues, and hOGG1 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analysis of buccal cell DNA isolated from 169 Caucasian orolaryngeal cancer cases and 338 race-, sex- and age-matched controls. hOGG1 mRNA was detected in all aerodigestive tract tissues tested including tonsil, tongue, floor of mouth, larynx and esophagus. Significantly increased risk for orolaryngeal cancer was observed for both the hOGG1 326(Ser)/326(Cys) (odds ratio [OR] = 1.6, 95% confidence interval [CI] = 1.04-2.6) and hOGG1 326(Cys)/326(Cys) (OR = 4.1, 95% CI = 1.3-13) genotypes. Although no significant difference in risk for orolaryngeal cancer was observed for hOGG1 genotypes in never-smokers, increased risk for orolaryngeal cancer was observed for subjects with the homozygous polymorphic hOGG1 326(Cys)/326(Cys) genotype in smokers (>100 cigarettes lifetime; OR = 4.8, 95% CI = 1.3-18). Similarly, although no association was observed in never drinkers of alcohol, significantly increased risk was observed for the hOGG1 326(Cys)/326(Cys) genotype in alcohol drinkers (>1 shot/week; OR = 6.9, 95% CI = 1.6-29). These results suggest that hOGG1 may play an important role in the repair of 8-OH-dG adducts in the aerodigestive tract and that the hOGG1 Ser326Cys polymorphism plays an important role in risk for smoking- and alcohol-related orolaryngeal cancer.
Carcinogenesis 2002 Jul
PMID:The human OGG1 DNA repair enzyme and its association with orolaryngeal cancer risk. 1211 82

The contribution of oxidative stress, different types of DNA damage and expression of DNA repair enzymes in colon and liver mutagenesis induced by 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) was investigated in four groups of six Big Blue rats fed diets with 0, 20, 70, and 200 mg IQ/kg for 3 weeks. There were dose-response relationships of DNA adducts ((32)P-postlabeling) and DNA strand breaks (comet assay) in colon and liver tissues, with the highest levels of DNA adducts and strand breaks in the colon. There was dose-dependent induction of mutations in both the colon and the liver, and the same IQ dose produced two-fold more cII mutations in the liver compared with the colon. The IQ-induced mutation spectrum in the colon was not significantly different to that of control rats. The expression of ERCC1 and OGG1 was higher in the colon than liver, and was unaffected by the IQ diet. Investigations of oxidative stress biomarkers produced inconclusive results. Oxidative DNA damage detected by the endonuclease III enzyme and 7-hydro-8-oxo-2'-deoxyguanosine in colon, liver and/or urine was unaltered by IQ. However, there was increased level of gamma-glutamyl semialdehyde in liver proteins, indicating a higher rate of protein oxidation in the liver following IQ administration. In plasma and erythrocytes there were unaltered levels of oxidized protein, malondialdehyde, and antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, catalase, glutathione reductase) indicating no systemic oxidative stress. However, the level of total vitamin C was increased in plasma, with the largest fraction being in the reduced form. In conclusion, our results indicate that DNA adducts rather than oxidative stress are responsible for the initiation of IQ-induced carcinogenesis of the liver and colon. A lower frequency of mutations in the colon than in the liver could be related to higher expression of DNA repair enzymes in the former.
Carcinogenesis 2002 Aug
PMID:Mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in colon and liver of Big Blue rats: role of DNA adducts, strand breaks, DNA repair and oxidative stress. 1215 58

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. Nine samples were collected from each subject over a period of 52 days. Sampling took place from January to May. The mRNA levels of OGG1 and ERCC1 correlated closely (r = 0.86, P << 0.0001) after normalization to either 18S ribosomal RNA or to beta-actin mRNA. The levels of OGG1 and ERCC1 mRNA were relatively constant within an individual with intra-individual correlation (R(2) = 0.45-0.46) in a General Linear Model. The amounts of ERCC1 and OGG1 relative to 18S RNA were doubled in May compared with January. This coincided with an increase in the monthly influx of sunlight from 18 MJ/m(2) in January to 242 MJ/m(2) in May. The mRNA levels of both ERCC1 and OGG1 were positively correlated to the average daily influx of sunlight in the previous 30 and 5 days (r = 0.49; r = 0.37, respectively, P << 0.001). There were no significant effects of the dietary interventions. The inter-individual variation was 5-10-fold, which is more than the observed 2-3-fold seasonal variation. Thus, despite seasonal variation of the individual mRNA levels, the inter-person variation is still far larger than the intra-person variation, supporting the use as biomarkers.
Carcinogenesis 2002 Sep
PMID:Inter-individual variation, seasonal variation and close correlation of OGG1 and ERCC1 mRNA levels in full blood from healthy volunteers. 1218 94

Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. To establish our overall understanding of possible in vivo relationships between DNA repair polymorphisms and the development of cancer, we performed a literature review of epidemiological studies that assessed associations between such polymorphisms and risk of cancer. Thirty studies of polymorphisms in OGG1, XRCC1, ERCC1, XPC, XPD, XPF, BRCA2, and XRCC3 were identified in the April 30, 2002 MEDLINE database (National Center for Biotechnology Information. PubMed Database: http://www.ncbi.nlm.nih.gov/entrez). These studies focused on adult glioma, bladder cancer, breast cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head and neck, and stomach cancer. We found that a small proportion of the published studies were large and population-based. 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. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings. We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of cancer in the presence of reduced DNA repair capacity.
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PMID:Polymorphisms in DNA repair genes and associations with cancer risk. 1249 39

Oxidatively damaged bases in the genome are likely to be responsible for mutations leading to sporadic carcinogenesis. Two structurally similar DNA glycosylases, NTH1 and OGG1, which are able to excise most of these damaged bases, were identified previously in mammalian cells. A distinct family, consisting of two human DNA glycosylases orthologous to enzymes in Escherichia coli, has recently been characterized; they have overlapping substrate ranges with NTH1 and OGG1. The presence of multiple enzymes with potential back-up functions underscores the importance of removing both endogenously and exogenously generated oxidatively damaged bases from the genome, and may explain why no cancer or other disease phenotype has so far been linked to the deficiency of a single DNA glycosylase.
Carcinogenesis 2003 Feb
PMID:The discovery of a new family of mammalian enzymes for repair of oxidatively damaged DNA, and its physiological implications. 1280 39

Cancers may develop in the background of genomic instability with accumulated mutations. Helicobacter pylori gastritis is characterized by acute foveolitis of the proliferative zone, which is found in any stage of the gastritis as long as the infection persists. Because acute foveolitis targets specifically the proliferative zone of pits, the proliferating epithelial cells are under severe and persistent mutagenic pressure. In H. pylori gastritis, a characteristic morphological change of epithelial cells, the malgun (clear) cell change is frequently present in association with acute foveolitis. Malgun cells have enlarged euchromatic nuclei and abundant cytoplasm. The expression of proliferating cell nuclear antigen and cytokeratin 8 are typically up-regulated in them indicating that they are mitotically and metabolically active. Here, we report evidence for DNA damage and repair in malgun cells. Significant double-strand DNA breaks were shown by the consistent terminal dUTP nick-end labeling in the nuclei of malgun cells. Proteins related to DNA damage and repair, such as Ku, poly(ADP-ribosyl) polymerase, OGG1, and MSH2 were selectively up-regulated in malgun cells. Inducible nitric oxide synthase was also up-regulated. There were occasional bcl2- and p53-expressing cells suggesting that further steps of carcinogenesis took place at the single cell level. Our results suggest that the malgun cell change represents a characteristic morphological sign of cellular genomic damage and repair, and may be implicated in an early stage of carcinogenesis. It is suggested that acute foveolitis of the proliferative zone is a major pathogenetic step of gastric carcinogenesis in H. pylori gastritis.
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PMID:Malgun (clear) cell change in Helicobacter pylori gastritis reflects epithelial genomic damage and repair. 1265 12

DNA oxidation is a potential cause of cancer in humans. It is well-known that fruits and vegetables protect against cancer, and this may be in part because they contain antioxidants, which decrease the level of oxidation of DNA. However, there are other possible mechanisms, such as an enhancement of cellular repair of this damage. A randomized cross-over study was carried out on healthy human subjects, who were given kiwifruit as a supplement to their normal diet, for 3-week periods at different 'doses', with 2-week washout periods between doses. Endogenous oxidation of bases in lymphocyte DNA, and the resistance of the DNA to oxidation ex vivo, were assessed using single cell gel electrophoresis (the 'comet assay'). The capacity to repair DNA base oxidation was measured with an in vitro test, and levels of expression of repair-related genes OGG1 and APE1 were assessed by semi-quantitative RT-PCR. Concentrations of dietary antioxidants were measured in plasma. The antioxidant status of plasma and of lymphocytes was increased by consumption of kiwifruit. Levels of endogenous oxidation of pyrimidines and purines in DNA were markedly decreased, and DNA repair measured on a substrate containing 8-oxo-7,8-dihydroguanine was substantially increased (without change in levels of OGG1 or APE1 mRNA). The magnitude of these effects was generally not related to the number of kiwifruits consumed per day. Kiwifruit provides a dual protection against oxidative DNA damage, enhancing antioxidant levels and stimulating DNA repair. It is probable that together these effects would decrease the risk of mutagenic changes leading to cancer.
Carcinogenesis 2003 Mar
PMID:Nutritional modulation of DNA repair in a human intervention study. 1266 12


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