Summary
Simple directly acting alkylating agents can be classified in terms of their mutagenic efficiency and their chemical reactivity. The most mutagenic are the N-nitroso compounds and these have a preference for reacting with nucleic acid oxygens in vitro and in vivo. In contrast, the alkyl sulfates are generally poor mutagens and react almost exclusively with base nitrogens. Other classes of alkylating agents also show correlations between oxygen reaction and mutagenicity. Ethylating agents are more oxygen-specific than the analogous methylating agent and, in a substantial number of cases, also more mutagenic at lower levels of treatment.
Sites of substitution by ethyl nitroso compounds (e,g., N-ethyl-N-nitrosourea, N-ethyl-N’ -vitro-N-nitrosoguanidine) in doublestranded nucleic acids are as follows: phosphate ≫ N7-G > 02-T, 06-G > N3-A > 04-T, 02-C > other N. In single-stranded nucleic acids the reactivity of the 02 of C, Nl of A, and N3 of U, T, or C is considerably greater. Certain of these derivatives have been shown in in vitro transcription or ribosome binding studies to mispair; namely, 02-alkyl T, 04-alkyl T, 06-alkyl G, 02-alkyl C, 3-alkyl C, 3-alkyl U or T, and 1-alkyl A. In all cases, nonspecif is mispairing occurs with high frequency. During in vivo replication such errors are probably relatively rare but nevertheless postulated to occur.
There is evidence that various types of repair enzymes exist in bacteria and mammalian cells that can remove, to varying extents, N-3 and N-7 alkyl purines, O6-alkyl G, 02-alkyl T, 0 -alkyl T, and 02-alkyl C. Phosphotriesters in DNA appear to be very stable.
When substitution occurs on a site necessary for basepairing or in a site causing steric hindrance or electronic shielding of Watson-Crick sites, the result is ambiguity in transcription rather than termination. It is hypothesized that any or all unrepaired promutagenic lesions can be expressed as errors during replication.
Other mutagens described in terms of their chemical reactions and repair include simple nonalkylating agents, most of which change basepairing due to deamination or tautomeric shifts and the metabolic products of aromatic amines and polyaromatic hydrocarbons.
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Singer, B. (1982). Mutagenesis from a Chemical Perspective: Nucleic Acid Reactions, Repair, Translation, and Transcription. In: Lemontt, J.F., Generoso, W.M. (eds) Molecular and Cellular Mechanisms of Mutagenesis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-3476-7_1
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