Nitrosated peptides and polyamines as endogenous mutagens in O6-alkylguanine-DNA alkyltransferase deficient cells.
Mutants of Escherichia coli and Saccharomyces cerevisiae that lack O6-alkylguanine-DNA alkyltransferase activities have increased spontaneous mutation rates, indicating the presence of a cellular metabolite that can alkylate DNA. Bacterially catalysed nitrosation has been implicated previously in producing the endogenous alkylating agent(s). Here, nitrosated polyamines and azaserine, a model compound for nitrosated peptides, are shown to be mutagenic to E. coli ada ogt mutants deficient in O6-alkylguanine-DNA alkyltransferase activity. The mutagenicity of azaserine may be explained by its ability to methylate DNA, whereas nitrosated spermidine causes DNA damage that is susceptible to both nucleotide excision repair and O6-alkylguanine-DNA alkyltransferase activity, which indicates the generation of more bulky DNA adducts. Nitrosated peptides and polyamines are therefore potential endogenous mutagens that are harmful particularly in O6-alkylguanine-DNA alkyltransferase deficient cells.
Sedgwick
B
B
Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Herts, UK.
D001377:Azaserine / Q000031:analogs & derivatives*; D002103:Cadaverine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase; D011073:Polyamines / Q000494:pharmacology*; D011700:Putrescine / Q000494:pharmacology; D013096:Spermine / Q000494:pharmacology
D011073:Polyamines; D008769:Methylnitronitrosoguanidine; D013096:Spermine; D001377:Azaserine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002103:Cadaverine; D011700:Putrescine