Characterization of molecular mechanisms governing budding yeast lifespan using small peptides that interact with the Anaphase Promoting Complex

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Evidence is accumulating that cellular lifespan correlates to its damage repair capacity. Genetic screens in model organisms, from yeast to flies, have consistently demonstrated that genes involved in stress response networks play a decisive role in lifespan determination. Using the brewing yeast model system, we have shown that regulated cell cycle progression is tightly linked with stress response and normal longevity. Our work characterizing the Anaphase Promoting Complex (APC) in yeast, a large highly conserved complex of proteins required for the targeting of substrates for ubiquitin-dependent degradation, has described a number of novel roles and substrates for the APC. The APC is largely known to target proteins that inhibit mitotic progression and G1 maintenance for degradation. Our studies over the past 15 years, many of them NSERC funded, have shown that the APC is also required for mitotic histone deposition and post-translational modifications, stress response, genomic stability, and lifespan. Our work therefore suggests that the APC plays a central and critical role in maintaining cell vigor and ultimately lifespan, leading to the hypothesis that increased APC activity will increase cellular stress response and lifespan. The research program described here will focus on isolating small peptides that bind to either the APC complex or to factors that influence APC function, to bring about increased stress response, cell vitality, and lifespan. We have performed genetic screens to isolate these small peptides and will focus on their characterization over the next funding period. This work is important, as we currently do not have a means to manipulate cellular stress response mechanisms to increase cell vitality and lifespan. Utilization of peptides that could increase APC activity and stress response may benefit any endeavor where environmental stresses have negative influences on cell well-being. The long-term goal of our research program is to obtain a comprehensive understanding of mechanisms that impact stress responses and cell lifespan. The research field within Canada will benefit through further expertise in research labs studying stress responses and cell vitality, by training HQP for academic and non-academic jobs. Our research program will provide solutions to problems where adaptions to environmental stresses are important, and may ultimately translate to an increased quality of life for Canadians and the world.