Abstract
Conditions of chronic stress are associated with genetic instability in many organisms, but the roles of stress responses in mutagenesis have so far been elucidated only in bacteria. Here, we present data demonstrating that the environmental stress response (ESR) in yeast functions in mutagenesis induced by proteotoxic stress. We show that the drug canavanine causes proteotoxic stress, activates the ESR, and induces mutagenesis at several loci in an ESR-dependent manner. Canavanine-induced mutagenesis also involves translesion DNA polymerases Rev1 and Polζ and non-homologous end joining factor Ku. Furthermore, under conditions of chronic sub-lethal canavanine stress, deletions of Rev1, Polζ, and Ku-encoding genes exhibit genetic interactions with ESR mutants indicative of ESR regulating these mutagenic DNA repair processes. Analyses of mutagenesis induced by several different stresses showed that the ESR specifically modulates mutagenesis induced by proteotoxic stress. Together, these results document the first known example of an involvement of a eukaryotic stress response pathway in mutagenesis and have important implications for mechanisms of evolution, carcinogenesis, and emergence of drug-resistant pathogens and chemotherapy-resistant tumors.
Highlights
Sensing and responding to environmental cues are ubiquitous cellular functions essential for survival
We present evidence that transcriptional activation of the environmental stress response (ESR) in the yeast S. cerevisiae can regulate mutagenesis elicited by several types of proteotoxic stress, including two amino acid analogs, canavanine and PFPA, and a drug that interferes with protein glycosylation, tunicamycin
The effect of the ESR was specific to proteotoxic stresses, as osmotic and DNA replication stresses elicited mutagenesis that was not affected by deletion of ESR activators, MSN2 and MSN4
Summary
Sensing and responding to environmental cues are ubiquitous cellular functions essential for survival. Budding yeast cells respond to a variety of stresses by inducing or repressing specific sets of genes in a stereotypical fashion that, to a certain degree, does not depend on the identity of the stress This process is termed the environmental stress response (ESR) [1,2]. The ESR provides little protection from the initiating stress – genes required to survive the stress do not significantly overlap those that change expression in response to the stress and mutations in ESR regulators do not significantly sensitize cells to stress [3,4] This observation raises the possibility that ESR activation may have other cellular roles. In this manuscript we investigate the effects of stress on mutagenesis in yeast and the role of the ESR in this process
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