The Yeast Environmental Stress Response Regulates Mutagenesis Induced by Proteotoxic Stress

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.

Environmentally responsive genome-wide accumulation of de novoArabidopsis thalianamutations and epimutations

“…1C), but similar to that of mutations accumulated in in vitro regenerant or irradiated A. thaliana lineages (Jiang et al 2011;Belfield et al 2012). Intriguingly, the change in Ti/Tv ratio generated by salt stress in A. thaliana is similar to that generated by the environmental stress response in yeast (Shor et al 2013). Furthermore, the ;1.7 Ti/Tv ratio is comparable with that of natural variant SNPs (;1.6) (Cao et al 2011), suggesting that environmental factors (e.g., stresses) may substantially affect the molecular spectrum of mutations arising de novo in Arabidopsis lineages growing in nature.…”

“…However, the extent to which this increased accumulation is passive (an incidental consequence of stress exposure) versus active (an organismally regulated response to environmental stress) is not currently clear (see below for further discussion). In some cases, organisms exposed to environmental stress actively alter the rates and patterns with which de novo genetic (and possibly epigenetic) variants arise, in turn potentially promoting long-term evolu- Shor et al 2013). This concept is exemplified by the well-known bacterial SOS response mechanism (Bjedov et al 2003;Baer et al 2007;Rando and Verstrepen 2007) and by related SIM mechanisms (Baer et al 2007;Bindra et al 2007;Al Mamun et al 2012;Shor et al 2013).…”

“…Possible mechanisms for alteration in DNA repair in A. thaliana plants grown on saline soils include stress-related impairment of DNA repair activity or potential up-regulation of the error-prone polymerases typical of the SOS and SIM mechanisms identified in bacteria, yeast, and human cancer cells (Baer et al 2007;Bindra et al 2007;Rando and Verstrepen 2007;Al Mamun et al 2012;Shor et al 2013). …”

“…However, the natural environment is rarely as benign as these laboratory environments, and plants growing in nature are frequently exposed to varying combinations of environmental stresses (Easterling et al 2000;Parmesan and Yohe 2003;Mittler 2006). Furthermore, the phenomenon of stress-induced mutagenesis (SIM), in which mutation is promoted when cells are poorly adapted to their environment, is well established in bacteria (Al Mamun et al 2012) and more recently identified in yeast and human cancer cells (Bindra et al 2007;Shor et al 2013). We therefore sought to determine if propagation of A. thaliana MA lineages in a stressful environment changes the rates and profiles of de novo variant accumulation, reasoning that such changes could have important implications for the understanding of plant genome evolution in nature.…”

Stress-induced mutagenesis and complex adaptation

“…This scenario has an important biological relevance, as SIM has been implicated in the evolution of drug resistance in bacteria and yeast [34,70,71], and could be involved in the evolution of pathogen virulence and the evolution of drug resistance and progression in cancer cells [72]. We assume that after the environmental change, the SIM e population has reached a new MSB [56] with mutation rate tU, before the appearance of the double mutant (with s ¼ 0.05 and U ¼ 0.0004, for example, the average number of deleterious mutations is 0.99 .…”