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Among the best studied examples of DNA amplification, as a response to drug selection, is the increased DHFR gene copy number observed in tumor cells resistant to methotrexate (MTX)1,2,. In spite of numerous studies into the mechanism of DHFR gene amplification in a variety of cell types, we do not yet have a detailed understanding of the molecular events which initiate the amplification process. Moreover, in spite of a relative wealth of information about the distribution and arrangement of amplicons observed in MTXR cells, we know very little about endogenous factors which affect the frequency of DHFR amplification-nor do we understand, at the molecular level, the process of resolution of early events into the final amplicon structures observed in drug-resistant cells.

High concentrations of deoxythymidine monophosphate (dTMP) induce mutations in Saccharomyces cerevisiae. Strains defective in the RAD6 gene-thought to be involved in error-prone DNA repair-do not show dTMP-induced mutation. We propose a model to explain these findings and suggest that fluxes of thymidine nucleotides may diminish the fidelity of DNA replication.

During early meiotic development the yeast Saccharomyces cerevisiae has a characteristic nuclear dense body (NDB). It is shown that the NDB can also be induced in vegetatively growing cells through the inhibition of thymidylate synthetase which causes depletion of the dTMP pool and arrests DNA synthesis. The observations on NDBs and recombination levels suggest that thymidylate-stressed cells may activate parts of the meiotic pathway and, conversely, cells on sporulation medium may sense, among other things, reduced thymidylate levels and respond to the several stimuli by entering the meiotic pathway.