Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The repair of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-produced O6-methylguanine (O6-MeG) in DNA and its correlation with MNNG-produced cell-killing and sister chromatid exchange (SCE) induction were compared in mouse and reference human tumor cell strains. As a result, mouse cell strains were divided into three groups: (i) cells proficient in O6-MeG-repair and insensitive to MNNG similar to human Mer+ Rem+ strains; (ii) cells deficient in O6-MeG-removal and sensitive to MNNG similar to human Mer-Rem- strains; (iii) cells deficient in O6-MeG-removal but insensitive to MNNG similar to some SV40-transformed human strains. Attempts at correlating lack of capacity for O6-MeG-removal, MNNG-sensitivity and high SCE induction showed that O6-MeG in DNA may be a lesion common to cell-killing and SCE induction only in mouse cells of groups i and ii. Levels of O6-MeG-DNA methyltransferase activity in mouse cells were measured and the enzyme had the same molecular weight as that in human cells.
Carcinogenesis 1984 May
PMID:Comparison of repair of O6-methylguanine produced by N-methyl-N'-nitro-N-nitrosoguanidine in mouse and human cells. 672 79

O6-Methylguanine-DNA methyltransferase activity, i.e., the capacity of cells to transfer the methyl group from O6-methylguanine in DNA to protein, was determined in 10 hepatoma cell lines, all derived from Reuber H35 hepatoma but differing in their status of differentiation. Methyltransferase activity of the six differentiated lines tested was at least 4-5 times higher than that of two dedifferentiated lines. The activity of the two poorly differentiated lines examined was low to intermediate. Some of the differentiated lines possessed methyltransferase activities comparable to those in hepatocytes freshly isolated from adult rat. The results suggest that certain differentiated hepatoma lines are capable of mimicking liver in the capacity for repair of O6-methylguanine lesions and in this respect may be useful as model systems for studying liver-specific effects of monofunctional alkylating agents.
Carcinogenesis 1984 Jul
PMID:The capacity of rat hepatoma cell lines for O6-methylguanine-DNA repair correlates with their status of differentiation. 673 58

A rapid assay of O6-MeG-DNA methyltransferase activity is described. Following incubation of cell extracts with O6-[3H]MeG-containing DNA, remaining radioactive DNA was hydrolyzed in trichloroacetic acid and separated from methylated radioactive protein by filtration or centrifugation. Transfer of radioactive methyl from DNA to protein was proportional to the amount of protein added, and was not linear with time. More than 90% of the radioactivity precipitated after acid hydrolyses was in S-methyl cysteine residues. The method was used to measure O6-MeG-DNA methyltransferase activity in extracts of 24 neoplastic tissues from human organs. Although five tumor tissues had 28-84% lower activity of O6-MeG-DNA methyltransferase than the corresponding normal tissue from the same patient, higher or similar levels of activity were found more frequently. Thus, a lack of O6-MeG-DNA methyltransferase activity in human tumours appears not to be a frequent event. The DNA repair enzyme uracil-DNA glycosylase was also measured in the same extracts. Most frequently the level of uracil-DNA glycosylase activity was essentially similar in tumors and normal tissues but significantly higher or lower levels were also observed.
Carcinogenesis 1984 Aug
PMID:A simplified assay for O6-methylguanine-DNA methyltransferase activity and its application to human neoplastic and non-neoplastic tissues. 674 14

Ethionine, the hepatocarcinogenic antimetabolite of methionine, was fed to rats in carcinogenic doses for 1-10 weeks. Levels of 5-methyldeoxycytidine (5-MC) in nuclear DNA and total cellular levels of S-adenosylmethionine (AdoMet) and S-adenosylethionine (AdoEt) were determined at 1, 5 and 10 weeks in livers of control and ethionine-treated animals. The percentage of deoxycytidine residues modified to 5-MC in hepatic DNA of ethionine-fed animals was the same as that in the control animals at 1 week but was 3.6% and 7.6% lower than that observed in control animals at 5 and 10 weeks, respectively. Significant levels of AdoEt, a DNA methylase inhibitor, as well as decreases in the levels of AdoMet were also observed in the livers of ethionine-fed animals. In a second study, the levels of 5-MC, AdoMet and AdoEt were determined in the pancreas, kidneys, testes and thymus of control rats and rats fed ethionine for 10 weeks. Only the testes, an organ known to be susceptible to the toxic effects of ethionine, showed a significant (p less than 0.02) decrease in 5-MC in response to ethionine feeding. AdoEt was present in all tissues studied, except thymus, but at lower levels than those observed in the liver. These results demonstrate that ethionine administration alone under conditions which cause tumors is sufficient for the production of hypomethylated DNA in the target organ and one extrahepatic tissue studied. Hypomethylation of hepatic DNA would appear to result from the accumulation of AdoEt coupled with the decreased levels of AdoMet.
Carcinogenesis 1984 Aug
PMID:Hypomethylation of DNA in ethionine-fed rats. 674 18

The direct-acting carcinogens N-acetoxy-N-acetyl-2-aminofluorene (AcAAF), methyl nitrosourea (MNU), and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were tested for their ability to inhibit highly purified, rat liver DNA methylase in vitro. Fifty percent inhibition of DNA methylase activity was achieved with 4.3 mM AcAAF, 47 mM MNU and 2.8 mM MNNG. When the enzyme was reassayed in the presence and absence of dithiothreitol, it was shown that DNA methylase was protected by increasing amounts of the thiol reducing agent. When other thiol reducing agents were tested for their ability to protect DNA methylase from carcinogen damage, a differential protective ability was observed. Dithiothreitol, beta-mercaptoethanol, and reduced glutathione were effective in protecting DNA methylase from carcinogen inhibition, while the effect of cysteine was intermediary and the effect of ergothioneine was minimal. These results may be related to the hypomethylation of DNA observed in several cancers, suggesting that the carcinogens achieve this effect at least in part by inhibiting crucial sulfhydryl group(s) in the methylase molecule. These data also suggest that various intracellular thiols may play an important role in protecting DNA-modifying enzymes from carcinogen damage.
Carcinogenesis 1983 Sep
PMID:The protective role of thiol reducing agents in the in vitro inhibition of rat liver DNA methylase by direct acting carcinogens. 688 32

We have recently reported that following depletion of O6-methylguanine DNA methyltransferase (MGMT) activity by acute streptozotocin (STZ) treatment to sensitize innately chloroethylnitrosourea (CENU)-resistant HT-29 cells, the eventual repletion of activity occurs with no concommitant alterations in steady-state MGMT mRNA levels. This suggestion of a potentially stable transcript prompted studies to define the relative contributions of MGMT mRNA stability and transcription to cellular MGMT expression. Northern analysis of MGMT mRNA in actinomycin D-treated HT-29, MR-1 and A2182 cells, ranging in relative MGMT expression from high to low respectively, demonstrates relatively long MGMT mRNA half-lives of > 10-12 h. Cell lines with low and moderate levels of MGMT mRNA appear to have longer mRNA half-lives than those with high levels. Run-on transcription in nuclei isolated from cells with low to moderate MGMT mRNA levels demonstrates undetectable basal MGMT transcription rates. Collectively these data suggest that a very low transcription rate, coupled with a stable mRNA molecule, might result in the translation of pre-existing mRNA molecules. This translation may be responsible for the gradual recovery of MGMT and CENU resistance over 24 h following MGMT depletion.
Carcinogenesis 1995 Sep
PMID:The role of mRNA stability and transcription in O6-methylguanine DNA methyltransferase (MGMT) expression in Mer+ human tumor cells. 755 86

Dietary folate/methyl deficiency provides a unique model of endogenous hepatocarcinogenesis in which to study progressive alterations in DNA methylation patterns during tumor progression in vivo. Weanling male F344 rats were given a semi-purified diet deficient in the methyl donors choline, methionine and folic acid for a period of 9 weeks. Using a genomic sequencing procedure based on the PCR amplification of bisulfite-modified DNA, the methylation status of individual CpG sites within exons 6 and 7 of the p53 gene in liver samples from control and deficient rats was determined. Treatment of denatured nuclear DNA with sodium bisulfite quantitatively converts all cytosine residues to uracil which are then amplified as thymine in the PCR reaction. In contrast, 5-methylcytosine is resistant to bisulfite deamination under the reaction conditions and is amplified as cytosine. Automated sequencing of bisulfite-modified DNA will then elucidate the methylation status of each cytosine residue within a defined gene sequence. In addition to evaluation of the methylation status of the p53 gene, the relative activity of the DNA methyltransferase was also quantified in nuclear extracts from control and folate/methyl deficient rats. The results indicate that specific 5-methyl cytosines within the hepatic p53 gene from methyl deficient rats are resistant to demethylation despite the diet-induced decrease in S-adenosylmethionine and the increase in cell proliferation associated with this dietary intervention. Progressive demethylation was observed at other methylated cytosine residues in folate/methyl deficient rats after 9 weeks despite a paradoxical increase in DNA methyltransferase activity. The application of this sequence-specific technology will allow the definition of the methylation status of every CpG site within a coding sequence or promoter region and should provide new insights into mechanisms and consequences of methylation dysregulation during progressive multistage carcinogenesis.
Carcinogenesis 1995 Nov
PMID:Differential sensitivity to loss of cytosine methyl groups within the hepatic p53 gene of folate/methyl deficient rats. 758 11

O6-Methylguanine-DNA methyltransferase (MGMT) plays an important role in protecting cells from the mutagenic potency of alkylating agents. This study addresses the role of DNA methylation in the expression of the human MGMT gene. Southern blot analysis of DNA from human Mer+ (MGMT proficient) and Mer- (MGMT deficient) cell lines demonstrated that the methylation state of a unique SmaI site in the MGMT gene promoter, previously shown by others to be invariably unmethylated in Mer+ cells and methylated in Mer- cells, did not correlate with the Mer phenotype. Neither was there any significant difference in the density of CpG methylation in the MGMT gene 5'-flanking sequences between Mer+ and Mer- cells. On the other hand, the body of the MGMT gene was less methylated in most Mer- cells relative to Mer+ cells, and in three of six Mer- cell lines the gene was essentially methylation-free. Interestingly, the Mer- cells that were hypomethylated in the MGMT gene also tended to be less methylated at other loci. Widespread hypomethylation is a frequent trait in carcinogenesis, and may be involved in development of the frequently found Mer- phenotype.
Carcinogenesis 1995 Aug
PMID:The methylation status of the gene for O6-methylguanine-DNA methyltransferase in human Mer+ and Mer- cells. 763 15

8-Hydroxyl-2'-deoxyguanosine (also referred to as 8-hydroxyguanine [8-OH-dG] or 7,8-dihydro-8-oxoguanine), a common DNA adduct resulting from injury to DNA via reactive oxygen species, affects the in vitro methylation of nearby cytosine moieties by the human DNA methyltransferase. The exact position of 8-OH-deoxyguanosine relative to a CpG dinucleotide appears important to this effect. Our data indicate that 8-OH-deoxyguanosine diminishes the ability of the methyltransferase to methylate a target cytosine when the 8-OH-deoxyguanosine is one or two nucleotides 3' from the cytosine, on the same strand. On the other hand 8-OH-deoxyguanosine does not diminish the ability of the enzyme to respond to a methyl director (5-methylcytosine) when the 8-OH-deoxyguanosine is on the same strand but one or two nucleotides 3' from the methyl director. Differences in methylation rates as great as 13-fold have been detected using various 8-OH-deoxyguanosine-containing oligonucleotides as substrates in methylation assays. Our findings suggest that oxidative damage of parental strand guanines would permit normal copying of methylation patterns through maintenance methylation, while oxidative damage of guanines in the nascent strand DNA would inhibit such methylation.
Carcinogenesis 1995 May
PMID:DNA adduct 8-hydroxyl-2'-deoxyguanosine (8-hydroxyguanine) affects function of human DNA methyltransferase. 776 94

Several studies have suggested that DNA hypomethylation is an early step in colorectal carcinogenesis. However, it is not clear at which stage in carcinogenesis this hypomethylation occurs, what promotes it, the extent to which it can be reversed and the consequences of such reversal in affecting tumour development. In an attempt to address some of these questions, we studied three groups of subjects with similar age and gender distributions: a group of 12 patients with colorectal carcinomas; a group of 12 patients with colorectal adenomas; and a group of eight healthy control subjects. Two experimental protocols were employed. In the first protocol, intrinsic DNA methylation was evaluated in neoplastic and in normal-appearing rectal mucosa of patients with colonic carcinomas or adenomas, compared with a group of healthy controls. In the second protocol, we examined, in a prospective and controlled fashion, the effect of folic acid supplementation (10 mg/day) on the degree of DNA methylation of rectal mucosa from those same patients after removal of the neoplasms. The degree of intrinsic DNA methylation was assessed on the basis of the capacity of the DNA isolates to serve as methyl acceptors in in vitro incubations that contained DNA methylase and [3H-methyl] S-adenosylmethionine. Intrinsic DNA methylation was significantly lower in carcinomas than in adenomas (P < 0.005). In addition, normal-appearing rectal mucosa from patients with carcinomas was significantly less methylated than in healthy controls (P < 0.005); the mean value found in the latter was also greater than the value observed in patients with adenomas, but not significantly so (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:DNA methylation as an intermediate biomarker in colorectal cancer: modulation by folic acid supplementation. 785 79


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