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PubMed1976

The methylation of tRNA.

The methylation of tRNA is a post-transcriptional modification which is achieved by specific enzymes, the tRNA methylases, with S adenosylmethionine as a methyl donor. The level and pattern of methylation are characteristic of the tRNA species and origin. Abnormally methylated tRNAs have been obtained, in vivo and in vitro, by a variety of methods, and their properties have been studied. The tRNA methylases are found in all cells and tissues. Their activity varies with the differentiation state of the cells, and under the influence of many internal and external factors ; it is especially elevated in embryonic and cancerous tissues. These enzymes are very unstable, and none of them has been purified to homogeneity. We present here their known properties and we propose a theory concerning their specificity. Finally, after reviewing the few available experimental data, we discuss the current hypotheses and speculations about the roles and functions of tRNA methylation.

Animals↗
PubMed1984

Mature methyl-deficient tRNA isolated from a mammary adenocarcinoma.

A transplantable rat tumor, mammary adenocarcinoma 13762, accumulates tRNA which can be methylated in vitro by mammalian tRNA (adenine-1) methyltransferase. This unusual ability of the tumor RNA to serve as substrate for a homologous tRNA methylating enzyme is correlated with unusually low levels of the A 58-specific adenine-1 methyltransferase. The nature of the methyl-accepting RNA has been examined by separating tumor tRNA on two-dimensional polyacrylamide gels. Comparisons of ethidium bromide-stained gels of tumor vs. liver tRNA show no significant quantitative differences and no accumulation of novel tRNAs or precursor tRNAs in adenocarcinoma RNA. Two-dimensional separations of tumor RNA after in vitro [14C]methylation using purified adenine-1 methyltransferase indicate that about 25% of the tRNA species are strongly methyl-accepting RNAs. Identification of six of the tRNAs separated on two-dimensional gels has been carried out by hybridization of cloned tRNA genes to Northern blots. Three of these, tRNALys3 , tRNAGln and tRNAMeti , are among the adenocarcinoma methyl-accepting RNAs. The other three RNAs, all of which are leucine-specific tRNAs, show no methyl-accepting properties. Our results suggest that low levels of a tRNA methyltransferase in the adenocarcinoma cause selected species of tRNA to escape the normal A58 methylation, resulting in the appearance of several mature tRNAs which are deficient in 1-methyladenine. The methyl-accepting tRNAs from the tumor appear as ethidium bromide-stained spots of similar intensity to those seen for RNA from rat liver; therefore, methyladenine deficiency does not seem to impair processing of these tRNAs.

Adenocarcinoma↗
PubMed1981

tRNA chemical methylation. In vitro and in vivo formation of 1,7-dimethylguanosine at high concentrations of methylating agents.

The methylation patterns produced in Escherichia coli B tRNA by a range of concentrations of the weak carcinogen dimethyl sulphate were examined with the following results: 1. 1,7-Dimethylguanosine was found to be formed in high amounts in the tRNA methylation reaction at high concentrations of methylating agent. 2. The dialkylated compound was recovered mainly in the form of derivatives, the spectral and chromatographic behaviour of which varied according to the procedures used for their isolation. Similar results were obtained for the in vivo methylation of rat-liver tRNA: after administration of a very high dose of the powerful carcinogen dimethylnitrosamine, 1,7-dimethylguanosine was found in rat-liver tRNA. Moreover, the analysis of the time-course of nucleic acid methylation indicated that this dialkylated product was still present in rat-liver tRNA when the major product of alkylation, 7-methylguanine, had almost completely disappeared.

Alkylation↗
PubMed1978

Selective inhibition of uracil tRNA methylases of E. coli by ethionine.

L-ethionine has been found to inhibit uracil tRNA methylating enzymes in vitro under conditions where methylation of other tRNA bases is unaffected. No selective inhibitor for uracil tRNA methylases has been identified previously. 15 mM L-ethionine or 30 mM D,L-ethionine caused about 40% inhibition of tRNA methylation catalyzed by enzyme extracts from E. coli B or E. coli M3S (mixtures of methylases for uracil, guanine, cytosine, and adenine) but did not inhibit the activity of preparations from an E. coli mutant that lacks uracil tRNA methylase. Analysis of the 14CH3 bases in methyl-deficient E. coli tRNA after its in vitro methylation with E. coli B3 enzymes in the presence or absence of ethionine showed that ethionine inhibited 14CH3 transfer to uracil in tRNA, but did not diminish significantly the 14CH3 transfer to other tRNA bases. Under similar conditions 0.6 mM S-adenosylethionine and 0.2 mM ethylthioadenosine inhibited the overall tRNA base methylating activity of E. coli B preparations about 50% but neither of these ethionine metabolites preferentially inhibited uracil methylation. Ethionine was not competitive with S-adenosyl methionine. Uracil methylation was not inhibited by alanine, valine, or ethionine sulfoxide. It is suggested that the thymine deficiency that we found earlier in tRNA from ethionine-treated E. coli B cells, resulted from base specific inhibition by the amino acid, ethionine, of uracil tRNA methylation in vivo.

Amino Acids↗
PubMedDate not supplied

Theorectical mechanisms for synthesis of carcinogen-induced embryonic proteins: III. The tRNA methylases; methylation mechanism and function.

It is contended that redundant repressed tRed) with carcinogens in adult cells. Supportive evidence, especially from molecular model building, is presented for a mechanism of tRNA methylation. In this mechanism the adenine moiety of S-adenosyl-L-methionine base-pairs with uracil for all tRNA methylations. Furthermore it is proposed that such methylations are required during the transcription of a tRNA molecule in order to limit the number of possible conformers that can occur before further development of the molecule takes place. This theory of the function for methyl groups is discussed in the light of the properties found for hypomethylated tRNAs.

Animals↗
PubMedDate not supplied

[Methylation of rat liver tRNA under different experimental conditions].

The primary biochemical and conformational changes in tRNA of the albino rat liver were studied under conditions of X-ray irradiation and under the effect of prozerine and nicotinic acid. Under the effect of these factors the rate of the liver tRNA methylation increases by 45, 103 and 112%, respectively. The melting point of the tRNA control preparations is 61 degrees C, under the the effect of irradiation--57 degrees C, under the prozerine and nicotinic acid effect--52 degrees C. Hyperchromia of the tRNA control and experimental preparations is equal to 28, 30 and 34%, respectively. No changes were found in sedimentation coefficient of the tRNA control and experimental preparations.

Animals↗
PubMed1980

Cerebellar tRNA methyltransferases: a developmental study.

Developmental patterns of homologous and heterologous tRNA methylation by cerebellar tRNA methyltransferases are described. The study revealed that: (a) homologous tRNA methylation results in the predominant formation of N2-methylguanine and 1-methyladenine; (b) tRNA methyltransferase of bulk-isolated Purkinje and granule cells methylate E. coli tRNAglu2 in vitro in a characteristic manner, and (c) the methylation of 8-day-old cerebellar, cortical and hepatic tRNA in vivo yields tRNAs containing different proportions of methylated bases. The findings suggest that the presumably cell-specific populations of cerebellar tRNA methyltransferases continue to alter their substrate recognition characteristics up to and beyond the first month of post-natal life.

Aging↗
PubMed2006

Catalysis by the second class of tRNA(m1G37) methyl transferase requires a conserved proline.

The enzyme tRNA(m1G37) methyl transferase catalyzes the transfer of a methyl group from S-adenosyl methionine (AdoMet) to the N1 position of G37, which is 3' to the anticodon sequence and whose modification is important for maintaining the reading frame fidelity. While the enzyme in bacteria is highly conserved and is encoded by the trmD gene, recent studies show that the counterpart of this enzyme in archaea and eukarya, encoded by the trm5 gene, is unrelated to trmD both in sequence and in structure. To further test this prediction, we seek to identify residues in the second class of tRNA(m1G37) methyl transferase that are required for catalysis. Such residues should provide mechanistic insights into the distinct structural origins of the two classes. Using the Trm5 enzyme of the archaeon Methanocaldococcus jannaschii (previously MJ0883) as an example, we have created mutants to test many conserved residues for their catalytic potential and substrate-binding capabilities with respect to both AdoMet and tRNA. We identified that the proline at position 267 (P267) is a critical residue for catalysis, because substitution of this residue severely decreases the kcat of the methylation reaction in steady-state kinetic analysis, and the k(chem) in single turnover kinetic analysis. However, substitution of P267 has milder effect on the Km and little effect on the Kd of either substrate. Because P267 has no functional side chain that can directly participate in the chemistry of methyl transfer, we suggest that its role in catalysis is to stabilize conformations of enzyme and substrates for proper alignment of reactive groups at the enzyme active site. Sequence analysis shows that P267 is embedded in a peptide motif that is conserved among the Trm5 family, but absent from the TrmD family, supporting the notion that the two families are descendants of unrelated protein structures.

Amino Acid Sequence↗