Methionine reduces spontaneous and alkylation-induced mutagenesis in Saccharomyces cerevisiae cells deficient in O6-methylguanine-DNA methyltransferase.
The exposure of DNA to reactive intracellular metabolites is thought to be a major cause of spontaneous mutagenesis. DNA alkylation is implicated in the above process by the fact that bacterial and yeast cells lacking DNA alkylation-specific repair genes exhibit elevated spontaneous mutation rates. The origin of the intracellular alkylating molecules is not clear; however, S-adenosylmethionine (SAM) has been proposed as one source because it has a reactive methyl group known to methylate proteins and DNA. We supplemented yeast cultures with excess methionine and examined the effects of increased endogenous SAM concentration on spontaneous and alkylation-induced mutagenesis in the absence of various DNA repair pathways. Our results show that either the excess methionine, or the increased SAM produced as a result of this treatment, is able to protect yeast cells from mutagenesis, and that this effect is alkylation-damage-specific. The protective effect was observed only in the mgt1 mutant deficient in the O(6)-methylguanine-DNA repair methyltransferase, but not in the wild type or other DNA repair-deficient strains, indicating that the protection is specific for O-methyl lesions. Thus, our results may lend support to the recently reported chemopreventive effect of SAM in rodents and further suggest that the observed tumor prevention by SAM may be, in part, due to its suppression of spontaneous mutagenesis in mammals. Given that a strong correlation has been established between O(6)-methylguanine and carcinogenicity, this study may offer a novel approach to preventing carcinogenesis.
Bawa
S
S
Department of Microbiology and Immunology, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada.
Xiao
W
W
D000478:Alkylation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004271:DNA, Fungal / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008715:Methionine / Q000378:metabolism / Q000494:pharmacology*; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D016296:Mutagenesis / Q000187:drug effects*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000172:deficiency* / Q000235:genetics*; D010084:Oxidation-Reduction; D012436:S-Adenosylmethionine / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*
D004271:DNA, Fungal; D008769:Methylnitronitrosoguanidine; D012436:S-Adenosylmethionine; D008715:Methionine; D019853:O(6)-Methylguanine-DNA Methyltransferase