Role ofRAS2in Recovery from Chronic Stress: Effect on Yeast Life Span

The replicative life span ofSaccharomyces cerevisiaewas previously shown to be modulated by the homologous signal transducers Ras1p and Ras2p in a reciprocal manner. We have used thermal stress as a life span modulator in order to uncover functional differences between theRASgenes that may contribute to their divergent effects on life span. Chronic exposure of cells throughout life to recurring heat shocks at sublethal temperatures decreased their replicative life span.ras2mutants, however, suffered the largest decrease compared to wild-type andras1mutant cells. The decrease was correlated with a substantial delay in resumption of budding upon recovery from these heat shocks, indicating an impaired renewal of cell cycling. Detailed analysis of gene expression showed that, during recovery,ras2mutants were selectively impaired in down-regulation of stress-responsive genes and up-regulation of growth-promoting genes. Our results suggest that one of the functions ofRAS2in maintaining life span, for whichRAS1does not substitute, is to ensure renewal of growth and cell division after bouts of stress that cells encounter during their life. This activity ofRAS2is effected by the cyclic AMP pathway. Overexpression ofRAS2,but notRAS2^ser42which is deficient in the activation of adenylate cyclase, completely reversed the effect of chronic stress on life span. Thus,RAS2is limiting for longevity in the face of chronic stress. SinceRAS2is known to down-regulate stress responses, this demonstrates that for longevity the ability to recover from stress is at least as important as the ability to mount a stress response.