scholarly journals Alkylation of deoxyribonucleic acid by carcinogens dimethyl sulphate, ethyl methanesulphonate, N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea. Relative reactivity of the phosphodiester site thymidylyl(3′-5′)thymidine

1978 ◽  
Vol 171 (3) ◽  
pp. 575-587 ◽  
Author(s):  
D H Swenson ◽  
P D Lawley
Keyword(s):  
Alkyl Group ◽  
Deoxyribonucleic Acid ◽  
Dimethyl Sulphate ◽  
Alkylating Agents ◽  
Electrophilic Reagent ◽  
Relative Reactivity ◽  
Ethyl Methanesulphonate ◽  
A Value ◽  
Phosphodiester Group ◽  
Steric Accessibility

1. The ethyl phosphotriester of thymidylyl(3′-5′)thymidine, dTp(Et)dT, was identified as a product from reaction of DNA with N-ethyl-N-nitrosourea, by procedures parallel to those reported previously for the methyl homologue produced by N-methyl-N-nitrosourea. 2. Enzymic degradation to yield alkyl phosphotriesters from DNA alkylated by these carcinogens and by dimethyl sulphate and ethyl methanesulphonate was studied quantitatively, and the relative yields of the triesters dTp(Alk)dT were determined. The relative reactivity of the phosphodiester group dTpdT to each of the four carcinogens was thus obtained, and compared with that of DNA overall, or with that of the N-7 atom of guanine in DNA. Relative reactivity of the phosphodiester group was lowest towards dimethyl sulphate, the least electrophilic of the reagents used, and was highest towards N-ethyl-N-nitrosourea, the most electrophilic reagent. 3. The nature of the alkyl group transferred also influenced reactivity of the phosphodiester site, since this site was relatively more reactive towards ethylation than would be predicted simply from the known Swain-Scott s values of the alkylating agents. It was therefore suggested that the steric accessibility of the weakly nucleophilic phosphodiester group on the outside of the DNA macromolecule favours its reaction with ethylating, as opposed to methylating, reagents. 4. Taking a value of the Swain-Scott nucleophilicity (n) of 2.5 for an average DNA nucleotide unit [Walles & Ehrenberg (1969) Acta Chem. Scand. 23, 1080-1084], a value of n of about 1 for the phosphodiester group was deduced, and this value was found to be 2-3 units less than that for the N-7 atom of guanine in DNA. 5. The reactivity of DNA overall was markedly high towards the alkylnitrosoureas, despite their relatively low s values. This was ascribed to an electrostatic factor that favoured reaction of the negatively charged polymer with alkyldiazonium cation intermediates.

The influence of radiomimetic substances on deoxyribonucleic acid synthesis and function studied in Escherichia coli / phage systems V. A comparison of the inactivation of phages T 2, T 7 and two strains of T 4 by alkylating agents

1959 ◽  
Vol 151 (942) ◽  
pp. 148-155 ◽  
Keyword(s):  
Deoxyribonucleic Acid ◽  
Osmotic Shock ◽  
Alkylating Agents ◽  
Acid Synthesis ◽  
Acid Moiety ◽  
Rate Of Penetration ◽  
Injection Process ◽  
Deoxyribonucleic Acid Synthesis ◽  
And Function ◽  
Escherichia Coli Phage

The sensitivity of phage T 7 to epoxides and freshly prepared solutions of di(2-chloroethyl) methylamine ( HN 2) was identical with that of T 2. T 7, however, proved considerably the more sensitive to ethylenimine and to aged solutions of HN 2. It was considered that this was due to the cationic nature of these latter agents affecting the rate of penetration into the phage heads, and that the susceptibility of T 2 and resistance of T 7 to osmotic shock was a parallel phenomenon. Confirmation was afforded by the fact that a strain of T 4 sensitive to osmotic shock behaved like T 2, and a resistant strain of T 4 like T 7. These results, together with others previously reported, are believed to offer very strong evidence that inactivation of bacteriophage by alkylating agents derives from reaction with the deoxyribonucleic acid moiety, probably leading to a failure of the injection process.

scholarly journals Cytogenetic and complementation analyses of recessive lethal mutations induced in the X chromosome of Drosophila by three alkylating agents

1974 ◽  
Vol 24 (1) ◽  
pp. 1-10 ◽  
Author(s):  
J. K. Lim ◽  
L. A. Snyder
Keyword(s):  
Drosophila Melanogaster ◽  
Salivary Gland ◽  
X Chromosome ◽  
Alkylating Agents ◽  
Complementation Analysis ◽  
Ethyl Methanesulphonate ◽  
Induced Mutations ◽  
Recessive Lethal ◽  
Lethal Mutations

SUMMARYSalivary-gland chromosomes of 54 methyl methanesulphonate- and 50 triethylene melamine-induced X-chromosome recessive lethals in Drosophila melanogaster were analysed. Two of the lethals induced by the mono-functional agent and 11 of those induced by the polyfunctional agent were found to be associated with detectable aberrations. A complementation analysis was also done on 82 ethyl methanesulphonate- and 34 triethylene melamine-induced recessive lethals in the zeste-white region of the X chromosome. The EMS-induced lethals were found to represent lesions affecting only single cistrons. Each of the 14 cistrons in the region known to mutate to a lethal state was represented by mutant alleles, but in widely different frequencies. Seven of the TEM-induced lethals were associated with deletions, only one of which had both breakpoints within the mapped region. Twenty-six of the 27 mutations in which only single cistrons were affected were mapped to 7 of the 14 known loci. One TEM- and two EMS-induced mutations were alleles representing a previously undetected locus in the zeste-white region.

scholarly journals The reaction of alkylating agents with bacteriophage R17. Biological effects of phosphotriester formation

1974 ◽  
Vol 137 (2) ◽  
pp. 313-317 ◽  
Author(s):  
Kenneth V. Shooter ◽  
Ruth Howse ◽  
R. Kenneth Merrifield
Keyword(s):  
Reaction Mechanism ◽  
Biological Effects ◽  
Alkylating Agents ◽  
Hydrolysis Reaction ◽  
Ethyl Methanesulphonate ◽  
Neutral Ph ◽  
Rate Of Hydrolysis ◽  
Alkylation Reactions ◽  
Kinetics Of ◽  
Hydrolysis Of

The extent of biological inactivation and of the degradation of the RNA after reaction of bacteriophage R17 with ethyl methanesulphonate, isopropyl methanesulphonate and N-ethyl-N-nitrosourea was studied. Formation of breaks in the RNA chain probably results from hydrolysis of phosphotriesters formed in the alkylation reactions. Near neutral pH the ethyl and isopropyl phosphotriesters are sufficiently stable for the kinetics of the hydrolysis reaction to be followed. Results indicate that the rate of hydrolysis increases rapidly as the pH is raised. The evidence shows that a phosphotriester group does not itself constitute a lethal lesion. The extent of phosphotriester formation by the different agents is discussed in terms of reaction mechanism.

scholarly journals Molecular mechanisms in alkylation mutagenesis. Induced reversion of bacteriophage T4rII AP72 by ethyl methanesulphonate in relation to extent and mode of ethylation of purines in bacteriophage deoxyribonucleic acid

1975 ◽  
Vol 145 (1) ◽  
pp. 85-91 ◽  
Author(s):  
P D Lawley ◽  
C N Martin
Keyword(s):  
Molecular Mechanisms ◽  
Deoxyribonucleic Acid ◽  
Single Site ◽  
Ethyl Methanesulphonate ◽  
Induce Mutation ◽  
Single Burst

Survival and reversion to T4r+ of bacteriophage T4rII AP72 after treatment with ethyl methanesulphonate at 37 degrees or 45 degrees C were studied in relation to the extent and mode of alkylation of purines in DNA of ethylated bacteriophage. A single-burst technique was used for reversion assay. Survival was lower at 45 degrees C than at 37 degrees C at a given extent of ethylation of bacteriophage DNA, confirming that events subsequent to ethylation, probably depurinations, are the main cause of decreased survival. Reversion was positively correlated (approximately linearly except at low extents at 37 degrees C) with ethylation of bacteriophage DNA, showing that ethylation itself causes mutation. Following the concept that reversion results from G-C leads to A-T transition at a single site (Krieg, 1963a,b) and the suggestion that O6-alkylation of guanine generates the miscoding base (Loveless, 1969), it was calculated that about one-third of induced O6-ethylguanines at this site would miscode to induce mutation.

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