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)

Azacitidine is a pyrimidine ring analog of cytidine that is incorporated into RNA causing alteration in RNA synthesis and processing and resulting in inhibition of protein synthesis. Azacitidine as the deoxynucleotide is also incorporated into DNA inhibiting its synthesis and blocking cytosine methylation by noncompetitive inhibition of DNA methyltransferase. The resulting hypomethylation of DNA is thought to induce gene activation and expression and cell differentiation. This may be an underlying factor in azacitidine's antileukemic activity and also contributes to its carcinogenic and tumor-promoting properties in experimental models.
Cancer Treat Rep 1987 Oct
PMID:Biochemistry of azacitidine: a review. 244 43

Enzymatic methylation of mammalian DNA is closely related to the replication process; also, the synthesis of DNA methylase, an enzyme that is responsible for this process, is cell cycle related. A monoclonal antibody against DNA methylase recognizes proliferatively active cells in the heterogeneous population. We used this antibody to identify the proliferative state of different cell types in normal vaginal smears and in smears of patients with precancerous lesions and cervical cancer. In all preparations, the normal epithelial cells remained unstained. The majority of cancer cells gave a positive immunocytochemical signal indicating the presence of DNA methylase antigen and the proliferative state. Staining was also observed in dyskaryotic cells, particularly in nuclei of parabasal-type cells.
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PMID:Immunocytochemical staining of different cell types in vaginal smears by monoclonal anti-DNA methylase antibodies. 307 7

DNA methylation in eukaryotic cells is a post-replicative process involving the transfer of methyl groups from S-adenosyl-L-methionine to the 5 position of cytosine residues through the action of DNA (cytosine-5-)-methyltransferase (DNA-methylase). There are two types of methylation within the cell: a maintenance methylation and a de novo methylation. Its major function is the maintenance methylation of hemimethylated sites after replication in order to preserve the pattern from one generation to the next. Nevertheless DNA-methylase is also able to transfer methyl groups to unmethylated sites in various substrates in a de novo reaction. Male Sprague-Dawley rats have a low specific activity of liver maintenance DNA-methylase and are sensitive to the toxic and carcinogenic effects of N-hydroxy-N-acetylaminofluorene (N-OH-AAF). Female Sprague-Dawley rats, on the contrary, have a 4-5 times higher maintenance DNA-methylase activity and are 6-7 times less sensitive to this carcinogenic effect. Their de novo DNA-methylase activity is the same. When female Sprague-Dawley rats are treated with N-OH-AAF their total DNA-methylase activity diminishes. On the contrary, the maintenance DNA-methylase activity of male Sprague-Dawley rats increases, whereas the de novo activity remains constant. In the spleen, which is not a target organ, the total DNA-methylase activity decreases after injection of N-OH-AAF. These variations of DNA-methylase activity are due to a variation of extractable nuclear DNA-methylase. When Swiss mice, which are not sensitive to the carcinogenic effect, are treated with N-OH-AAF, their total DNA-methylase activity decreases. A decrease of DNA-methylase activity in response to this carcinogen seems to be correlated to the resistance of the animals in developing a hepatocarcinoma.
Cancer Lett
PMID:Variations of DNA-(cytosine-5-)-methyltransferase activities after administration of N-hydroxy-N-aminofluorene to Sprague-Dawley rats. 318 39

The effect of nutritional zinc-deficiency on the activities of O6-alkylguanine:DNA methyltransferase (AGT) in 9 rat tissues including liver, lung, kidney, spleen, brain, esophagus, forestomach, gastric-stomach and small intestine has been examined. Individual tissue extracts prepared from zinc-deficient and pair-fed, zinc-sufficient rats were incubated with N-[3H]methylnitrosourea-methylated calf thymus DNA for 1 h. The activities of AGT in these tissues were measured by two methods: (a) the transfer of the methyl group from O6-methylguanine in substrate DNA to AGT protein, and (b) the determination of the ratio of O6-methylguanine:7-methylguanine remaining in substrate DNA following incubation. AGT activities (expressed as fmol protein methylated/h per mg protein) were significantly reduced in the esophagus, spleen and lungs of zinc-deficient rats as compared to those in their corresponding zinc-sufficient counterparts. The ratio of O6-methylguanine:7-methylguanine was also reduced in the esophagus of the zinc-deficient rat. These results were consistent with our earlier findings that dietary zinc-deficiency enhances nitrosamine-induced esophageal carcinogenesis in rats.
Cancer Lett 1988 Nov
PMID:Effect of nutritional zinc-deficiency on O6-alkylguanine-DNA-methyl-transferase activities in rat tissues. 319 74

O6-Methylguanine DNA methyltransferase (O6-MT) is considered to play an important role in the repair of alkylating carcinogen-induced lesions in a wide range of mammalian species. Fish are used widely in cancer research, one advantage being their high sensitivity to a variety of alkylating agents. To throw light on the mechanisms of DNA repair in the hitherto uninvestigated fish group, O6-MT activity was measured in liver from eight fish species belonging to six classes. Levels of O6-MT activity comparable with mouse values were found in liver of Japanese medaka (Oryzias latipes). Relatively low, but appreciable, levels of O6-MT activity were also observed in the other seven species examined. No adaptive increase in enzyme activity could be established in liver of rainbow trout following chronic dimethylnitrosamine pretreatment.
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PMID:O6-methylguanine DNA methyltransferase activity in liver from various fish species. 360 94

The activity of de novo DNA (cytosine-5-)-methyltransferase (DNA methylase) in various rat tissues after administration of a single dose of N-methyl-N-nitrosourea (MNU) has been analyzed. The total and specific activities of the DNA methylase of the brain, where tumor induction is important, are increased. In kidney, the DNA methylase activity first increases up to 16 h and decreases afterwards. Liver DNA methylase activity does not change. This organ is not susceptible to MNU induced cancers. Because organs in which the DNA methylase activity is high or increased after MNU are more prone to carcinogenesis by this compound, we argue that there is a relationship between the effects of MNU and DNA methylase activity.
Cancer Res 1986 Mar
PMID:Changes in de novo DNA (cytosine-5-)-methyltransferase activity in oncogenically susceptible rat target tissues induced by N-methyl-N-nitrosourea. 394 88

One of the most readily quantitated indices of myeloid maturation in HL-60 cells is their ability to respond to the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate with increased respiratory burst activity. HL-60 cells exposed to the antileukemic drug, 5-azacytidine (3 to 5 microM) for 24 hr and subsequently cultured in its absence for 2 to 3 days develop an enhanced ability to respond to 12-O-tetradecanoylphorbol-13-acetate with increased respiratory burst activity detectable as an increase both in hexose monophosphate shunt activity and in the proportion of the population producing superoxide anion. 5-Azacytidine treatment also causes marked inhibition of DNA methyltransferase, and thus DNA synthesized by HL-60 cells during the 24-hr period of analogue treatment is essentially devoid of methylated cytosine residues. This suggests, as does our previous finding that a general inhibitor of transmethylation reactions, L-ethionine, can induce differentiation of HL-60 cells, that changes in gene expression triggered by these compounds may be linked to their ability to alter patterns of DNA methylation. Since at least 50% of HL-60 cells capable of forming colonies in soft agar after a 24-hr exposure to 5-azacytidine yield progeny that mature (i.e., produce superoxide anion in response to 12-O-tetradecanoylphorbol-13-acetate) 2 weeks after 5-azacytidine treatment, the results also indicate that the changes induced in HL-60 cells by limited exposure to 5-azacytidine are heritable and can influence gene expression many generations after treatment has been terminated.
Cancer Res 1983 Feb
PMID:Effect of 5-azacytidine on differentiation and DNA methylation in human promyelocytic leukemia cells (HL-60). 618 56

The relationship between antineoplastic activity of 5-aza-2'-deoxycytidine (5-aza-dCyd) in mice with L1210 leukemia and inhibition of DNA methylation was investigated. BALB/c X DBA/2 F1 mice with L1210 leukemia were given a 15-hr i.v. infusion of 5-aza-dCyd at a total dose ranging from 0.5 mg/kg (weak antineoplastic effect) to 22 mg/kg (very potent antineoplastic effect). The DNA of L1210 leukemia cells was isolated from 5-aza-dCyd-treated mice and tested for its ability to accept methyl groups from S-adenosyl-L-methionine in a reaction catalyzed by DNA methyltransferase. The methyl-accepting ability of leukemia cell DNA was found to be dependent on the dose of 5-aza-dCyd, suggesting that this therapy induced significant changes in the level of methylation of the DNA. At the start of the 5-aza-dCyd infusion, mice were given i.p. injections of [6-3H]uridine, and the DNA of the L1210 leukemia cells was isolated at the end of therapy. Analysis of the labeled pyrimidine bases showed that 5-aza-dCyd produced a dose-dependent reduction in the 5-methylcytosine content of the DNA. Thus, there appears to be a correlation between the antileukemic activity of 5-aza-dCyd and its ability to inhibit DNA methylation.
Cancer Res 1983 Aug
PMID:Inhibition of DNA methylation in L1210 leukemic cells by 5-aza-2'-deoxycytidine as a possible mechanism of chemotherapeutic action. 619 May 53

The E2a region of the Ad2 genome encodes the Ad2-specific DBP. An inverse correlation between the level of DNA methylation at the 5'-CC*GG-3' sites of the E2a region and the extent of expression of DBP has been demonstrated in Ad2-transformed hamster cell lines (Vardimon et al. 1980). Four different leaders are used in the transcription of the E2a region in cells productively infected with Ad2. The leader located at coordinate 75 on the viral genome is used early after infection and the other three leaders are used late after infection (Chow et al. 1979). The analysis of the integration patterns of the viral DNA in the Ad2-transformed cell lines has revealed that the early leader is deleted in the cell lines which do not express the DBP (Vardimon and Doerfler 1981). The late leader located at coordinate 72 on the viral genome is present. The region encoding that late leader has been subcloned, and the cytoplasmic RNA from the cell line which expresses the DBP has been analyzed. It has been shown that the late leader is used in transformed cells. Hence the absence of the early leader cannot be the immediate reason for the lack of expression of the DBP. Correlations between DNA methylation and the absence of gene expression may indicate that methylation regulates gene expression or that methylation is the consequence of lacking gene expression. In order to decide between these alternatives an in vitro system has been employed. The HindIII A fragment of the Ad2 DNA which encodes the DBP has been methylated in vitro by the HpaII DNA methyltransferase. Methylated or unmethylated HindIII A fragment has been microinjected into the nuclei of Xenopus laevis oocytes. Unmethylated HindIII A fragment has been found to be expressed as specific viral RNA, whereas no viral RNA can be found in oocytes microinjected with methylated HindIII A fragment. The possibility of a nonspecific inhibitory factor in the methylated DNA preparation has been ruled out by the simultaneous microinjection of sea urchin histone gene DNA together with the methylated HindIII A fragment. Histone genes are expressed, while the expression of the methylated viral gene is blocked. By using the single-strand-specific endonuclease S1 we have shown that in Xenopus laevis oocytes initiation of transcription of the E2a region starts exactly at the same site as in Ad2 productively infected cells. These results provide direct evidence for the notion that DNA methylation at specific sites is involved in the regulation of gene expression.
Recent Results Cancer Res 1983
PMID:Can DNA methylation regulate gene expression? 630 51

We propose a general model for neoplastic development which postulates that the loss of methyl groups from 5-methylcytosines (5-mC) involved in the control of gene expression may initiate neoplastic transformation and give rise to the aberrant phenotype of the transformed cell. Interference with normal patterns of methylation can be envisioned to occur by a number of mechanisms: as a result of carcinogen-induced G:C leads to A:T transition leading to a loss of potentially methylatable cytosines; by mutations or chromosome rearrangement which disrupt the integrity of active DNA methylase genes; by separating methylated repressor regions of the genome from the genes they control; by direct interference with DNA methylation, as proposed for ethionine and 5-azacytidine; by spontaneous deamination of 5-mC to thymine, leading to accumulation of 5-mC:G leads to T:A transitions, by virus-induced perturbations in host cell methylation patterns; and by activation of DNA demethylases.
Br J Cancer 1983 Oct
PMID:5-Methylcytosine depletion during tumour development: an extension of the miscoding concept. 635 37


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