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

DNA in mammalian cells is enzymatically methylated at the 5-position of cytosine via S-adenosylmethionine and DNA methyltransferase. Several chemical carcinogens have been shown to inhibit this reaction, altering DNA methylation. We have been studying the mechanism by which carcinogens alter the methylation of DNA in order to better understand the cellular regulation of DNA methylase activity and to understand the role, if any, of DNA methylation in the carcinogenic process. We have utilized an in vitro assay for DNA methylase isolated from purified rat-liver nuclei. Ethionine, a liver carcinogen, given to rats 17 hr after partial hepatectomy inhibited the incorporation of [methyl-3H]-methionine into 5-methylcytosine residues of DNA. DNA isolated from these ethionine-treated rats was able to accept methyl groups from S-adenosylmethionine 8 times more than control DNA. It was further demonstrated that S-adenosylethionine competitively inhibited the DNA methylase resulting in hypomethylated DNA. N-Methyl-N-nitro-N-nitrosoguanidine reacted with the DNA methylase at the sulfhydryl sites inactivating the enzyme. Methylnitrosourea did not react directly with the methylase enzyme, but when reacted with DNA, the DNA methylase activity was inhibited by the carcinogen alkylated DNA. Sodium selenite also inhibited the enzyme non-competitively with a Ki of 6.7 microM. 5-Azacytidine prevented the 2 to 3 fold increase in DNA methylase seen 2 days following partial hepatectomy. All of these data with various carcinogens, altering DNA methylation by different mechanisms, support the hypothesis that DNA methylation plays a role in the initiation of carcinogenesis.
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PMID:Studies on DNA methyltransferase and alteration of the enzyme activity by chemical carcinogens. 243 29

Several restriction systems were detected in different strains of Streptomyces antibioticus by using actinophages as biological indicators. Adsorption of phages to the bacteria, together with the study of the efficiency of plating gave an initial indication of restriction in three strains. The alternation of efficiency of plating values obtained from restricting and nonrestricting hosts, gave evidence for the presence of a restriction-modification system in another strain. No common modification systems were detected among the different strains tested. Two specific endonucleases with a possible role in restriction were detected in strains ATCC 11891 and ETH 7451, respectively.
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PMID:Restriction-modification systems in Streptomyces antibioticus. 299 80

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.
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PMID:Hypomethylation of DNA in ethionine-fed rats. 674 18

A specific mechanism was given for ethionine-induced alpha-fetoprotein gene activity and is as follows: 1. Ethionine acts on competent cell types (e.g. stem cells) having one alpha-fetoprotein-enhancer-albumin gene region that is active and possesses embryonic-like low levels of S-adenosyl-L-methionine synthesis: DNA methylase genes for the enhancer regions are in the heterochromatic state. 2. ATP: L-methionine-S-adenosyltransferase acts upon ethionine and ATP to form S-adenosyl-L-ethionine; this lowers the amount of S-adenosyl-L-methionine synthesized and in turn also the synthesis of methyl-nicotinamide; the concentration of nicotinamide increases; there is an inhibition of polyADP ribosylation; hyporibosylation of histone 1 of nucleosomes; deblocking of embryonic type heterochromatin; and finally the second alpha-fetoprotein gene becomes activated. 3. Reversal occurs with the introduction of methionine; increase of S-adenosyl-L-methionine synthesis; increased methylnicotinamide synthesis; increased polyADP-ribose synthesis; ribosylation of H-1 protein to normal levels; and then the packing configuration of chromatin causes rerepression of alpha-fetoprotein genes. It is suggested that ethionine has the ability to perturb a methyl-sensitive heterochromatin that is peculiar to chromatin synthesized during embryogenesis. Therefore such repressed embryonic genes as alpha-fetoprotein are differentially susceptible to low concentrations of active methyl groups. Ethionine causes this hypomethylated heterochromatin by interference with S-adenosyl-L-methionine synthesis.
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PMID:A specific mechanism for ethionine-induced embryonic gene activity. 768 49