Genotoxicity of excess thymidylate in thymidylate low-requiring Saccharomyces cerevisiae is associated with changes in phosphate metabolism

Abstract

When dTMP in concentrations > 100 μM is offered to growing cells of thymidylate low-requiring yeast strains it is both mutagenic and toxic. At exposure concentrations > 1 mM dTMP interferes significantly with the low-affinity phosphate permease even in the presence of exogenous phosphate concentrations of 6 mM. Chemical analysis and 31P NMR spectroscopy reveal that excess dTMP distrubs metabolism in thymidylate low-requiring strains but not in the wild type. The most prominent changes in phosphorus-containing molecules are found in polyphosphates of which up to 20% are broken down within a 20-min time span with a concomitant increase in orthophosphate pools.