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

---

Query: EC:2.1.1.37 (DNA methyltransferase)
4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of chloroethylnitrosourea-resistant cells with streptozotocin (STZ) prior to bis-chloroethylnitrosourea (BCNU) exposure has been shown to result in a depletion of O6-methylguanine DNA methyltransferase (MGMT) activity, increased BCNU-induced interstrand cross-linking, and a 2-3 log enhancement of BCNU cytotoxicity in vitro. The current study was undertaken to define the kinetics of repletion of MGMT activity following the STZ/BCNU combination and to assess at the molecular level the effects of the combination on MGMT mRNA expression. Results demonstrate that MGMT activity can be depleted by greater than 90% relative to untreated controls using an optimized STZ/BCNU combination regimen and that greater than 50% depletion can be maintained for at least 24 h. This depletion appears to be independent of effects at the mRNA level because neither STZ alone nor the STZ/BCNU combination significantly altered steady state levels of MGMT mRNA. Cytotoxicity studies are consistent with MGMT repletion data and demonstrate that, as the interval between STZ and BCNU exposures increases, the degree of enhanced cytotoxicity induced by the combination relative to BCNU alone decreases. These results suggest that the enhanced cytotoxicity induced by the STZ/BCNU combination over BCNU treatment alone is favored by both the lack of induction of expression of MGMT mRNA and by slow reappearance of MGMT activity.
...
PMID:Effects of streptozotocin/bis-chloroethylnitrosourea combination therapy on O6-methylguanine DNA methyltransferase activity and mRNA levels in HT-29 cells in vitro. 182 18

The marginal level of clinical responses to the Chloroethylnitrosoureas (CENU, i.e. BCNU, CCNU, MeCCNU) suggests that there may exist an innate mechanism of resistance in tumors to these chemotherapeutic agents. A decade of research from many laboratories around the world has led to the identification of the mechanisms for tumor cell resistance to the CENU. The ability to prevent the formation of DNA interstrand crosslinks, thought to be the critical lethal lesion induced by these agents, is accomplished in a majority of human tumors by the unique DNA repair protein O-6 methylguanine DNA methyltransferase (MGMT). This review addresses the identification of this mechanism of resistance to therapy, and chemotherapeutic strategies to inhibit this DNA repair system, in an attempt to sensitize resistant tumors to the CENU.
...
PMID:The role of O-6 methylguanine DNA methyltransferase (MGMT) in drug resistance and strategies for its inhibition. 183 90

We have constructed derivatives of Escherichia coli that can be used for the rapid identification of recombinant plasmids encoding DNA restriction enzymes and methyltransferases. The induction of the DNA-damage inducible SOS response by the Mcr and Mrr systems, in the presence of methylated DNA, is used to select plasmids encoding DNA methyltransferases. The strains of E. coli that we have constructed are temperature-sensitive for the Mcr and Mrr systems and have been further modified to include a lacZ gene fused to the damage-inducible dinD locus of E. coli. The detection of recombinant plasmids encoding DNA methyltransferases and restriction enzymes is a simple, one step procedure that is based on the induction at the restrictive temperature of the lacZ gene. Transformants encoding DNA methyltransferase genes are detected on LB agar plates supplemented with X-gal as blue colonies. Using this method, we have cloned a variety of DNA methyltransferase genes from diverse species such as Neisseria, Haemophilus, Treponema, Pseudomonas, Xanthomonas and Saccharopolyspora.
...
PMID:A new method for the rapid identification of genes encoding restriction and modification enzymes. 185 62

Acute ethanol administration (3 g/kg twice a day) to pregnant mice, from the 9th thru the 11th day of gestation, resulted in hypomethylation of fetal deoxyribonucleic acid (DNA). Nuclei isolated from the fetuses of the ethanol-treated mice had lower levels of methylase activity relative to controls even in the presence of excess S-adenosylmethionine, which serves as the methyl donor for the enzyme DNA methyltransferase. Acetaldehyde, at concentrations as low as 3 to 10 microM, inhibited DNA methyltransferase activity in vitro. Since DNA methylation is thought to play an important role in the regulation of gene expression during embryogenesis, ethanol-associated alterations in fetal DNA methylation may contribute to the developmental abnormalities seen in the fetal alcohol syndrome.
...
PMID:Ethanol consumption inhibits fetal DNA methylation in mice: implications for the fetal alcohol syndrome. 187 25

Histones (from calf thymus or from human placenta), if renatured in the presence of EDTA, caused a severe inhibition of in vitro methylation of double-stranded DNA (from Micrococcus luteus) by human placenta DNA methyltransferase. The absence of EDTA during the histone renaturation procedure abolished--at least in the 'physiological' range of the histones/DNA ratio--the inhibition. The H1 component was responsible for this inhibition, no effect being exerted by the other histones. H1 preparations were more effective if renatured in the presence of EDTA--90% inhibition being reached at a 0.3:1 (w/w) H1/DNA ratio. It seems likely that the requirement for the presence of EDTA during the renaturation process is correlated to its ability to induce a fairly stable ordered conformation of the histones, although this effect could also be shown with the 'inactive' H2a, H2b and H3 components, and was instead less evident with histone H1. The restriction to histone H1 of the ability to inhibit enzymic DNA methylation may account for the lower methylation levels present in the internucleosomal DNA of mammalian chromatin.
...
PMID:Histones and DNA methylation in mammalian chromatin. Differential inhibition by histone H1. 188 42

A series of class-II restriction endonucleases (ENases) was discovered in the halophilic, phototrophic, gas-vacuolated cyanobacterium Dactylococcopsis salina sp. nov. The six novel enzymes are characterized by the following recognition sequences and cut positions: 5'-C decreases CRYGG-3' (DsaI); 5'-GG decreases CC-3' (DsaII); 5'-R decreases GATCY-3' (DsaIII); 5'-G decreases GWCC-3' (DsaIV); 5'-decreases CCNGG-3' (DsaV); and 5'-GTMKAC-3' (DsaVI), where W = A or T, M = A or C, K = G or T, and N = A, G, C or T. In addition, traces of further possible activity were detected. DsaI has a novel sequence specificity and DsaV is an isoschizomer of ScrFI, but with a novel cut specificity. A purification procedure was established to separate all six ENases, resulting in their isolation free of contaminating nuclease activities. DsaI cleavage is influenced by N6-methyladenine residues [derived from the Escherichia coli-encoded DNA methyltransferase (MTase) M.Eco damI] within the overlapping sequence, 5'-CCRYMGGATC-3'; DsaV hydrolysis is inhibited by a C-5-methylcytosine residue in its recognition sequence (5'-CMCNGG-3'), generated in some DsaV sites by the E. coli-encoded MTase, M.Eco dcmI.
...
PMID:A complex family of class-II restriction endonucleases, DsaI-VI, in Dactylococcopsis salina. 189 48

Binding of the EcoRII DNA methyltransferase to azacytosine-containing DNA protects the enzyme from digestion by proteases. The limit digest yields a product having a Mr on SDS-PAGE 20% less than the intact protein. The N terminus of the tryptic digestion product was sequenced and found to be missing the N terminal 82 amino acids. Under the conditions used unbound enzyme was digested to small peptides. Protection of the enzyme from protease digestion implies that the enzyme undergoes major conformational changes when bound to DNA. The trypsin sensitive region of the EcoRII methyltransferase occurs prior to the first constant region shared with other procaryotic DNA(cytosine-5)methyltransferases. To determine if this region played a role in substrate binding or specificity, N-terminal deletion mutants were studied. Deletion of 97 amino acids resulted in a decrease of enzyme activity. Further deletions caused a complete loss of activity. Enzyme deleted through amino acid 85 was purified and found to have the same specificity as wild type however there was an increase in Km for both S-adenosylmethionine (AdoMet) and DNA of 27 and 18 fold respectively. The N-terminus of the EcoRII methylase, although a variable region present in many procaryotic DNA(cytosine-5)methylases, plays no role in determining enzyme specificity, although it does contribute to the interaction with both AdoMet and DNA.
...
PMID:The core element of the EcoRII methylase as defined by protease digestion and deletion analysis. 192 25

O6-Methylguanine-DNA methyltransferase (O6-MT) is a DNA repair protein that reverses alkylation damage at the O6 position of guanine. In the process, O6-MT undergoes suicide inactivation. To determine if this enzyme might be regulated by pregnancy-associated hormones we measured changes in the level of O6-MT in isolated mouse mammary epithelial cell homogenates during different reproductive states. These were pregnancy, ectopic pituitary transplantation, proestrus/estrus and diestrus. O6-MT levels were found to be similar in mice in proestrus/estrus (0.95 fmol/micrograms DNA) as compared to diestrus (0.94 fmol/micrograms DNA) and also mixed populations of virgin mice (1.09 fmol/micrograms DNA). A mean for all virgin mice (0.97 fmol/micrograms DNA) was used as a comparative index. O6-MT decreased 2-fold during pregnancy in mammary epithelial cells to a mean value of 0.45 fmol/micrograms DNA (P less than 0.05). A smaller decrease (0.65 fmol/micrograms DNA; P less than 0.01) in mammary epithelial cells was found at 3 weeks following pituitary isograft. The repair capacity of mammary epithelial cells to liver was compared by measurements made in liver homogenates from the same mice and are approximately 3-fold higher in liver from virgin mice (3.2 fmol/micrograms DNA) than mammary gland. Liver levels of O6-MT increased in pregnant (5.3 fmol/micrograms DNA) and pituitary transplanted (3.9 fmol/micrograms DNA) mice, and were 5- and 4-fold higher than the concentration in virgin mammary epithelial cells respectively.
...
PMID:Cellular levels of O6-methylguanine-DNA methyltransferase in mammary epithelial cells and liver from virgin, pregnant and pituitary grafted mice. 193 59

Many bacterial species have adaptive responses which protect against the toxicity and mutagenicity of methylating agents. Induced 3-methyladenine-DNA glycosylase and O6-methylguanine-DNA methyltransferase activities increase the cellular capacity of E. coli, B. subtilis, and M. luteus to repair toxic and mutagenic methylated base derivatives in DNA. The DNA methyltransferase or Ada protein of E. coli regulates the response and is converted into a strong transcriptional activator by self-methylation on repair of a methylphosphotriester in DNA. The multiple functions of the E. coli Ada protein (39 kDa) are split between two proteins, AdaA (24 kDa) and AdaB (20 kDa), in B. subtilis. Proteins (39 kDa) recognised by anti-Ada antibodies are efficiently induced in several enterobacterial species and correlate with increased DNA methyltransferase activities. In contrast, an "Ada-related" protein is only weakly induced in Salmonella typhimurium and no increase in DNA repair activity is detectable. The existence of adaptive responses in diverged bacterial species suggests the frequent occurrence of methylating agents in the environment. Several direct-acting methylating agents which are known to arise in the environment have been shown to induce the response. These include abundantly occurring methyl chloride, the antibiotic streptozotocin, the precursors of the known labile inducers N-methyl-N'-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine and as shown in this paper, methyl radicals which may arise by the irradiation or oxidation of methyl compounds.
...
PMID:Widespread adaptive response against environmental methylating agents in microorganisms. 194 38

cDNA for O6-methylguanine-DNA methyltransferase was isolated by screening rat liver cDNA libraries, using as a probe the human cDNA sequence for methyltransferase. The rat cDNA encodes a protein with 209 amino acid residues. The predicted amino acid sequence of the rat methyltransferase exhibits considerable homology with those of the human, yeast and bacterial enzymes, especially around putative methyl acceptor sites. When the cDNA was placed under control of the lac promoter and expressed in methyltransferase-deficient Escherichia coli (ada-, ogt-) cells, a characteristic methyltransferase protein was produced. The rat DNA methyltransferase thus expressed could complement the biological defects of the E. coli cell caused by lack of its own DNA methyltransferases; e.g. increased sensitivity to alkylating agents in terms of both cell death and mutation induction.
...
PMID:Cloning and expresion of cDNA for rat O6-methylguanine-DNA methyltransferase. 194 35


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---