The influence of the mismatch-repair system on stationary-phase mutagenesis in the yeast Saccharomyces cerevisiae

Abstract

Stationary-phase (also called adaptive) mutation occurs in non-dividing cells during prolonged non-lethal selective pressure, e.g. starvation for an essential amino acid. Because in such conditions no DNA replication is observed, mutations probably arise as a result of inefficient DNA repair. In order to understand the role of the yeast mismatch-repair (MMR) system in the mutagenesis of stationary-phase cells, we studied the effects of deletions in genes encoding MutS- and MutL-related proteins on the reversion frequency of the lys2 Delta Bgl frameshift mutation. We found that the level of Lys(+) reversion was increased in all MMR mutants, with the strongest effect observed in a MSH2 (MUTS homologue)-deprived strain. Disruption of the MSH3 or MSH6 genes (also MUTS homologues) resulted in elevation of the mutation frequency and rate, but to a lesser degree than that caused by the inactivation of MSH2. MutL-related proteins were also required for mutation avoidance in stationary-phase cells, but to a lesser extent than MutS homologues. Among MutL homologues, Mlh1 seems to play the major role in this process, while Pms1 and Mlh3 are partially redundant and appear to substitute for each other. These data suggest that MMR proteins, particularly MutS homologues, are involved in the control of mutability in stationary-phase yeast cells.

Contribution of the Mismatch DNA Repair System to the Generation of Stationary-Phase-Induced Mutants of Bacillus subtilis

“…Results revealed that, in the absence of a functional MMR system, the mutant strain showed a clear propensity to increase the number of His ϩ , Met ϩ , and Leu ϩ colonies during stationary phase with respect to the number of revertants produced by the parental strain. In agreement with our results, the contribution of the MMR system in the adaptive mutation phenomenon was positively demonstrated in S. cerevisiae (8). Essentially, in that report the effects of each of the mutS and mutL homologs on the production of stationary-phase-associated mutants were independently tested and the strongest effect was obtained with an S. cerevisiae strain which lacked the MutS homolog MSH2 (8).…”

“…In agreement with our results, the contribution of the MMR system in the adaptive mutation phenomenon was positively demonstrated in S. cerevisiae (8). Essentially, in that report the effects of each of the mutS and mutL homologs on the production of stationary-phase-associated mutants were independently tested and the strongest effect was obtained with an S. cerevisiae strain which lacked the MutS homolog MSH2 (8).…”

“…While the loss of function of the MutL protein was proposed to be responsible for an MMR deficiency during the stationary phase of E. coli (9), the evidence presented in this report strongly suggests that the MutS protein is the nonfunctional component of the MMR system for the production of stationary-phase-induced mutants in B. subtilis. In S. cerevisiae, the other microorganism where the MMR system has been shown to play a role in stationaryphase-induced mutagenesis, MSH2, a MutS homolog, has been implicated as the major contributor to this type of mutagenesis (8).…”

“…While most of the research has involved Escherichia coli model systems, similar observations have been made in other prokaryotes (14,30) as well as in eukaryotic organisms (8). The most widely studied system thus far has been the FЈ lac frameshift-reversion construct of E. coli (25).…”

“…In addition to these findings in E. coli, a homolog of the MutS protein has also been found to be involved in the generation of stationary-phase-induced mutants in Saccharomyces cerevisiae (8).…”