The action of 1-nitroso-8-nitroprene in Eachericia coli: DNA adduct formation and mutational consequeces in the absence of necleotide excision-repair
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abstract
To study the mechanisms of mutagenesis by the carcinogen 1,8-dinitropyrene we have determined the DNA adducts formed and mutations induced by its partially activated metabolite 1-nitroso-8-nitropyrene (1,8-NONP) in an Escherichia coli strain deficient in nucleotide excision-repair. Using DNA sequence analysis we have characterized a collection of 159 lacI- mutations recovered following treatment with 1,8-NONP. The mutational spectrum was dominated by -1 frameshifts (110 events) in runs of contiguous G or C residues. Frameshift frequency was observed to increase with the length of the reiterated sequence. Two mutations involved the loss of GpC from alternating (GpC)n sequences. The ratio of -1:-2 events observed following 1,8-NONP treatment was markedly different from that induced by N-acetoxy-N-acetyl-2-aminofluorene in the same genetic target. Other mutational classes recovered included 'spontaneous' hotspot mutations (19 events), base substitutions (12 events), deletions (7 events), one duplication, one + (A:T) frameshift and one mutation containing closely juxtaposed -(G:C) events. Of the 125 point mutations characterized, 124 occurred at G:C sites. The site specificity of mutation was consistent with the 32P-postlabeling profile of 1,8-NONP-DNA adducts which showed that 95% of the adducts migrated to the same position on the TLC plates as the guanine C(8) adduct 1-N-(2'-deoxyguanosin-8-yl)-amino-8-nitropyrene. Two minor 1,8-NONP-DNA mutations were also detected, one at dG/dC sites, and the other at dA/dT sites.
