Mutator Suppression and Escape from Replication Error–Induced Extinction in Yeast

Cells rely on a network of conserved pathways to govern DNA replication fidelity. Loss of polymerase proofreading or mismatch repair elevates spontaneous mutation and facilitates cellular adaptation. However, double mutants are inviable, suggesting that extreme mutation rates exceed an error threshold. Here we combine alleles that affect DNA polymerase δ (Pol δ) proofreading and mismatch repair to define the maximal error rate in haploid yeast and to characterize genetic suppressors of mutator phenotypes. We show that populations tolerate mutation rates 1,000-fold above wild-type levels but collapse when the rate exceeds 10−3 inactivating mutations per gene per cell division. Variants that escape this error-induced extinction (eex) rapidly emerge from mutator clones. One-third of the escape mutants result from second-site changes in Pol δ that suppress the proofreading-deficient phenotype, while two-thirds are extragenic. The structural locations of the Pol δ changes suggest multiple antimutator mechanisms. Our studies reveal the transient nature of eukaryotic mutators and show that mutator phenotypes are readily suppressed by genetic adaptation. This has implications for the role of mutator phenotypes in cancer

Unveiling the infidelity problem in exclusive manufacturer-distributor relationships: A dyadic perspective

Infidelity has been a common dark-side phenomenon in manufacturer-distributor (M-D) relationships, which, despite its harmful effects on operating performance and long-term viability, has received scant theoretical and empirical attention in marketing research. Using data collected from 103 manufacturers and 101 distributors located in the USA, we investigate this phenomenon by conceptualizing it as a developmental process, comprising motives, symptoms, manifestations, consequences, and remedies. Our findings show that, with a few exceptions, there are no significant differences between manufacturers and distributors with regard to their perceptions of: (a) the structural, processual, and contextual factors contributing to the emergence of infidelity; (b) the behavioral and attitudinal factors helping to diagnose partner infidelity; (c) the ambiguous, explicit, and deceptive manifestations of infidelity; (d) the possible passive, mild, or aggressive consequences of infidelity; and (e) the pre-emptive or post hoc measures that need to be taken to cure infidelity

Identification of a mutant DNA polymerase delta in Saccharomyces cerevisiae with an antimutator phenotype for frameshift mutations.

We propose that a beta-turn-beta structure, which plays a critical role in exonucleolytic proofreading in the bacteriophage T4 DNA polymerase, is also present in the Saccharomyces cerevisiae DNA pol delta. Site-directed mutagenesis was used to test this proposal by introducing a mutation into the yeast POL3 gene in the region that encodes the putative beta-turn-beta structure. The mutant DNA pol delta has a serine substitution in place of glycine at position 447. DNA replication fidelity of the G447S-DNA pol delta was determined in vivo by using reversion and forward assays. An antimutator phenotype for frameshift mutations in short homopolymeric tracts was observed for the G447S-DNA pol delta in the absence of postreplication mismatch repair, which was produced by inactivation of the MSH2 gene. Because the G447S substitution reduced frameshift but not base substitution mutagenesis, some aspect of DNA polymerase proofreading appears to contribute to production of frameshifts. Possible roles of DNA polymerase proofreading in frameshift mutagenesis are discussed