Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Both DNA-AAF and MNU-alkylated DNA are methylated less than nonmodified DNA by rat brain nuclei cytosine 5-methyltransferase purified either by chromatography on DEAE cellulose or by Dyematrex. The inhibition of methylation is proportional to the modification of the DNA, and DNA having a given percentage of bases modified with MNU is less methylated than DNA modified to the same extent with AAF. Moreover, DNA-AAF irreversibly inhibits the methylation of native DNA, whereas MNU-alkylated DNA does not inhibit the methylation of native DNA. The AAF-substituted DNA has a higher affinity for the enzyme than native DNA. However, this is probably not due to the AAF-induced local destabilization of the DNA helix, since heat-denatured DNA shows a lower affinity for the enzyme than double-stranded DNA. Addition of DNA-AAF to the enzyme preincubated with native DNA inhibits methylation, but only after a lag period. This agrees with the model in which the methylase walks along the strand to methylate cytosine residues before being detached from the DNA. AAF bound to guanine residues may block the movement of the enzyme along the helix. The in vitro hypomethylation of DNA, caused by carcinogens, could explain the in vivo observations made by several authors and could have significance in gene activity, cellular differentiation, and oncogenesis.
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PMID:Enzymatic methylation of chicken erythrocyte DNA modified by two carcinogens, 2-(N-acetoxyacetylamino) fluorene and methylnitrosourea. 684 92

We demonstrate that DNA methylation in an adrenocortical tumor cell line, Y1, is controlled by the Ras signaling pathway. Forced expression of a cDNA encoding human GAP120 (hGAP), a down-modulator of Ras activity or delta 9-Jun a transdominant negative mutant of Jun, in Y1 cells reverts the transformed morphology of the cells and results in a reduction in the level of DNA methylation, DNA methyltransferase (MeTase) mRNA, and enzymatic activity. Introduction of an oncogenic Ha-ras into the GAP transfectants results in reversion to a transformed morphology and an increase in the levels of DNA methylation and DNA MeTase activity. Transient transfection CAT assays demonstrate that the expression of DNA MeTase promoter in Y1 cells is regulated by Ras and AP-1. These results establish a molecular link between a major signaling pathway involved in tumorigenesis and DNA methylation.
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PMID:Regulation of DNA methylation by the Ras signaling pathway. 774 70

O6-Methylguanine DNA methyltransferase (MGMT; EC 2.1.1.63) is an unusual DNA repair protein in that it directly and specifically repairs a premutagenic DNA lesion without involving other proteins. MGMT removes the alkyl group from O6-alkylguanine in DNA in a unique stoichiometric reaction by accepting the alkyl group on a cysteine residue. The intracellular level of MGMT varies among tissues and appears to be inversely correlated to tissue-specific tumorigenesis induced by monofunctional alkylating agents. Because MGMT acts in solo, genetic manipulation of its expression may provide valuable insight into its contribution to cellular resistance to alkylation toxicity and to tumor induction. The human MGMT full length cDNA has been fused with a portion of the human transferrin (TF) 5'-flanking region (TF/MGMT). Transgenic founder mice were produced carrying the TF/MGMT transgene and then bred to establish stable transgenic lines. Human MGMT transcripts were specifically expressed in abundance in transgenic brain and liver tissues. In vitro MGMT assays revealed approximately 150-fold and approximately 25-fold increases in MGMT activity in transgenic brain and liver extracts respectively. Western blot analysis confirmed that human MGMT protein is specifically synthesized in transgenic brain and liver tissues.
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PMID:Brain and liver targeted overexpression of O6-methylguanine DNA methyltransferase in transgenic mice. 835 38

In neoplastic cells, levels of DNA methyltransferase activity are often increased, and evidence is accruing to suggest an important role for this event in tumorigenesis. To evaluate this possibility further, and to investigate the contribution of increasing de novo, as opposed to maintenance, DNA methylation in mammalian cells, we expressed the bacterial HhaI methyltransferase in cultured murine fibroblasts. This enzyme is a pure de novo DNA methyltransferase that methylates the internal C in the sequence GCGC. We find that both constitutive and induced expression of the wild-type HhaI results, primarily, in lethality to the cells. However, surviving cell clones that express low levels of M. HhaI demonstrate increased tumorigenicity as assessed by soft agar cloning efficiency (8.6% for sense HhaI-transduced PA 317 cells versus 0.4% for antisense controls; 1.7% for sense HhaI-transfected NIH 3T3 cells versus 0% for a mutant HhaI control) and tumorigenicity in nude mouse heterotransplants (75% for sense HhaI-transduced PA 317 cells versus 18.5% for antisense controls). DNA isolated from the clonogenic sense HhaI clones, versus clones expressing the mutant HhaI gene, has no increase in overall CpG methylation but an average of 27% (range, 16.7-38.9) increase in methylcytosine content at GCGC sites. These findings suggest that eukaryotic cells tolerate a narrow window of increase de novo DNA methylating capacity, above which cell death occurs and within cell transformation results. Our results further emphasize the potential role of increased DNA methyltransferase activity in the evolution of cancer.
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PMID:Expression of prokaryotic HhaI DNA methyltransferase is transforming and lethal to NIH 3T3 cells. 856 81

Recent studies showing a correlation between the levels of DNA (cytosine-5-)-methyltransferase (DNA MTase) enzyme activity and tumorigenicity have implicated this enzyme in the carcinogenic process. Moreover, hypermethylation of CpG island-containing promoters is associated with the inactivation of genes important to tumor initiation and progression. One proposed role for DNA MTase in tumorigenesis is therefore a direct role in the de novo methylation of these otherwise unmethylated CpG islands. In this study, we sought to determine whether increased levels of DNA MTase could directly affect CpG island methylation. A full-length cDNA for human DNA MTase driven by the cytomegalovirus promoter was constitutively expressed in human fibroblasts. Individual clones derived from cells transfected with DNA MTase (HMT) expressed 1- to 50-fold the level of DNA MTase protein and enzyme activity of the parental cell line or clones transfected with the control vector alone (Neo). To determine the effects of DNA MTase overexpression on CpG island methylation, we examined 12 endogenous CpG island loci in the HMT clones. HMT clones expressing > or = 9-fold the parental levels of DNA MTase activity were significantly hypermethylated relative to at least 11 Neo clones at five CpG island loci. In the HMT clones, methylation reached nearly 100% at susceptible CpG island loci with time in culture. In contrast, there was little change in the methylation status in the Neo clones over the same time frame. Taken together, the data indicate that overexpression of DNA MTase can drive the de novo methylation of susceptible CpG island loci, thus providing support for the idea that DNA MTase can contribute to tumor progression through CpG island methylation-mediated gene inactivation.
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PMID:De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase. 875 56

This paper tests the hypothesis that cytosine DNA methyltransferase (DNA MeTase) is a candidate target for anticancer therapy. Several observations have suggested recently that hyperactivation of DNA MeTase plays a critical role in initiation and progression of cancer and that its up-regulation is a component of the Ras oncogenic signaling pathway. We show that a phosphorothioate-modified, antisense oligodeoxynucleotide directed against the DNA MeTase mRNA reduces the level of DNA MeTase mRNA, inhibits DNA MeTase activity, and inhibits anchorage independent growth of Y1 adrenocortical carcinoma cells ex vivo in a dose-dependent manner. Injection of DNA MeTase antisense oligodeoxynucleotides i.p. inhibits the growth of Y1 tumors in syngeneic LAF1 mice, reduces the level of DNA MeTase, and induces demethylation of the adrenocortical-specific gene C21 and its expression in tumors in vivo. These results support the hypothesis that an increase in DNA MeTase activity is critical for tumorigenesis and is reversible by pharmacological inhibition of DNA MeTase.
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PMID:Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligodeoxynucleotide. 901 45

The Min mouse, generated by random germline mutagenesis, carries a mutation in the mouse homolog of APC and is a model of inherited human intestinal tumorigenesis. To identify other genes in the pathway(s) of intestinal tumorigenesis, genes that modify the Min phenotype have been sought. Several have been identified, including Mom1 and the genes for the 5-cytosine DNA methyltransferase and the DNA mismatch repair factor Msh2. Min-dependent tumorigenesis also occurs in mammary glands, the pancreas, and the body wall. The Min mouse has therefore become a model for tumorigenesis in a variety of organs. Identifying modifiers of its phenotype will help in piecing together the pathways of tumorigenesis in each of these tissues.
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PMID:Manipulation of the mouse germline in the study of Min-induced neoplasia. 911 Apr 2

Cytosine methylation is an important mechanism of gene regulation in mammals. Mouse embryos with reduced DNA methylation due to targeted disruption of the DNA methyltransferase gene show deregulated expression of imprinted genes. Loss of imprinting associated with loss of allele-specific methylation is one example of an epigenetic alteration found in tumor cells. Changes in DNA methylation may also be associated with facilitating protooncogene expression and inactivating tumor suppressor genes. However, cytosine methylation has additional deleterious consequences for the genome as well. CpG dinucleotides, the target of DNA methylation, are five-fold underpresented in the genome due to the high mutability of methylated cytosine. C-T transition mutations resulting from deamination of 5-methylcytosine are involved in both genetic disease and cancer. Lastly, aberrant DNA methylation may promote the genetic instability of a chromosomal locus. We review the genetic and epigenetic roles for DNA methylation during tumorigenesis gleaned from altered methycytosine patterns in tumor cells, and from pharmacologic, dietary or genetic manipulation of DNA methylation levels.
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PMID:Experimental manipulation of genomic methylation. 911 Apr 3

Single-strand conformers (SSCs) from the C-rich strand of the triplet repeat at the FMR-1 locus are rapidly and selectively methylated by the human DNA (cytosine-5) methyltransferase. The apparent affinity of the enzyme for the FMR-1 SSC is about tenfold higher than it is for a control Watson-Crick paired duplex. The de novo methylation rate for the SSC is over 150-fold higher than the de novo rate for the control duplex. Methylation of what is generally called a hemi-methylated duplex occurs with a rate enhancement of over 100-fold, while methylation of what can be viewed as a hemi-methylated FMR-1 SSC is actually slower than the de novo rate. The pronounced inhibition of the methyltransferase by the methylated SSC suggests that the enzyme has a higher affinity for the methylated product of its reaction with the SSC than it has for the unmethylated SSC substrate. Gel retardation studies show that the methyltransferase binds selectively to SSCs from the C-rich strand of the FMR-1 triplet repeat. This suggests a two-step stalling process in which the human methyltransferase first selectively methlyates and subsequently stalls at the C-rich strand SSC. Stalling may reflect the inability of the enzyme to release a DNA product that is fixed in a conformation resembling its transition state by the unusual structure of the substrate. In particular, the data suggest that DNA methyltransferase may physically participate in biological processes that lead to dynamic mutation at FMR-1. In general, the data raise the possibility that a two-step stalling process occurs at secondary structures associated with chromosome instability, chromosome remodelling, viral replication or viral integration and may account for the local hypermethylation and global hypomethylation associated with viral and non-viral tumorigenesis.
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PMID:Stalling of human DNA (cytosine-5) methyltransferase at single-strand conformers from a site of dynamic mutation. 945 40

Molecular changes in the progressive state of tumorigenesis often include altered patterns of DNA methylation. Utilizing a series of breast epithelial cell lines, the overall 5-methylcytosine content in genomic DNA demonstrated an overall decrease when comparing two malignant cell lines (MCF-7 and T47D) with a mortal cell line (MCF 1 2M) and several derivative cell lines of the immortalized MCF10 cultures (MCF10A,-2A, -5A, A1neoT2, and 139B6). Further investigation on the methylation status of these cells lines indicated no difference in DNA methyltransferase activity, both at a protein and mRNA levels, in the nontumorigenic cell lines examined while activity was 3-10 fold higher in the tumorigenic lines (MCF7, T47D, SkBr3, MB-MDA-231, -468). Examination of the CpG island in the 5' promoter region of the estrogen receptor gene indicates that this region is unmethylated in the mortal and immortal nontumorigenic lines as well as the tumorigenic lines examined, with the exception of the estrogen receptor negative breast cell line MB-MDA-468 which appears to be partially methylated at this site. These results indicate methylation of this CpG island does not account for the inactivation of the estrogen receptor gene in immortalized nontumorigenic breast cells, suggesting another mechanism of transcriptional inactivation of ER in this environment.
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PMID:Examination of the DNA methylation properties in nontumorigenic and tumorigenic breast epithelial cell lines. 970 12


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