Uracil-DNA glycosylase activity affects the mutagenicity of ethyl methanesulfonate: evidence for an alternative pathway of alkylation mutagenesis.
Mutagenesis induced by the alkylating agent ethyl methanesulfonate (EMS) is thought to occur primarily via mechanisms that involve direct mispairing at alkylated guanines, in particular, O6-ethyl guanine. Recent evidence indicates that alkylation of guanine at the O-6 position might enhance the deamination of cytosine residues in the complementary strand. To determine whether such deamination of cytosine could play a role in the production of mutations by EMS, the efficacy of this agent was tested in uracil-DNA glycosylase deficient (Ung) strains of Escherichia coli. The Ung- strains showed a linear response with increasing doses of EMS. This response was independent of the umuC gene product. In contrast, the Ung+ strains yielded a dose-squared response that became linear at higher doses of EMS when the cells were defective for the umuC gene product. These results support a model for mutagenesis involving the deamination of cytosines opposite O6-alkylated guanines followed by an error-prone repair event.
Fix
D F
DF
Department of Biology, York University, Ont., Canada.
Koehler
D R
DR
Glickman
B W
BW
D045647:DNA Glycosylases; D004261:DNA Replication; D004269:DNA, Bacterial / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics*; D005020:Ethyl Methanesulfonate / Q000633:toxicity*; D007700:Kinetics; D008745:Methylation; D009152:Mutagenicity Tests; D009699:N-Glycosyl Hydrolases / Q000172:deficiency*; D013045:Species Specificity; D051981:Uracil-DNA Glycosidase
D004269:DNA, Bacterial; D005020:Ethyl Methanesulfonate; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase