N-Methyl-N′-nitro-N-nitrosoguanidine induced DNA sequence alteration; non-random components in alkylation mutagenesis |
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Authors: | Alasdair J E Gordon Philip A Burns and Barry W Glickman |
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Institution: | Department of Biology, York University, 4700 Keele Street, Toronto, Ont. M3J 1P3, Canada |
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Abstract: | Our approach to the study of how the molecular nature of DNA modulates the behavior of mutational sites involves the characterisation of distributions of mutations. The Escherichia coli lacI genetic/M13 cloning system allows the comparison of base substitution frequencies at a large number of sites. The observed distribution of N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)-induced G:C → A:T transition (the predominant event), and A:T → G:C transition (a relatively rare event), is strikingly non-random. Some sites of G:C → A:T mutation are almost 100 times more often mutated by MNNG than the least susceptible sites. Sites of mutation, however, do not display a continuum of mutability, but rather can be strictly demarcated by their 5′ flanking base. Sites with a high frequency of occurrence share a common sequence motif, namely 5′-R-G-N-3′, which is the sole apparent feature that distinguishes them from sites less commonly mutated (i.e. 5′-Y-G-N-3′). A corollary of this defined site specificity is the absence of a strand bias in MNNG-induced lacI−d mutation. The availability of specific or non-specific alkylation-repair systems does not appear to alter the distribution of mutation, which suggests that the observed mutational distribution is a direct reflection of the initial damage distribution. MNNG does not belong to that class of compounds typified by ultraviolet light or 4-nitroquinoline-N-oxide which exhibit both random and non-random components of mutagenesis. |
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Keywords: | N-Methyl-N′-nitro-N-nitrosoguanidine Escherichia coli lacI−d Mutational specificity Non-random mutant distribution DNA sequence alteration Alkylation mutagenesis |
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