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

越来越多的证据表明，细胞寿命与其损伤修复能力相关。从酵母到苍蝇等模式生物的基因筛查一直表明，参与应激反应网络的基因在决定寿命方面发挥着决定性作用。使用酿造酵母模型系统，我们已经表明，调控的细胞周期进展与应激反应和正常寿命密切相关。我们的工作描述了酵母中的后期促进复合体(APC)，这是一种大型的高度保守的蛋白质复合体，需要靶向底物进行泛素依赖的降解，描述了APC的一些新的作用和底物。众所周知，APC的目标蛋白是抑制有丝分裂进程和维持G1期降解的蛋白质。我们过去15年的研究，其中许多是由NSERC资助的，已经表明APC也是有丝分裂组蛋白沉积和翻译后修饰、应激反应、基因组稳定性和寿命所必需的。因此，我们的工作表明，APC在维持细胞活力和最终寿命方面发挥着核心和关键的作用，从而导致了APC活性增加将增加细胞应激反应和寿命的假说。这里描述的研究计划将集中于分离与APC复合体或影响APC功能的因子结合的小肽，以增加应激反应、细胞活力和寿命。我们已经进行了基因筛选来分离这些小肽，并将在下一个资金阶段重点研究它们的特性。这项工作很重要，因为我们目前还没有办法操纵细胞应激反应机制来增加细胞活力和寿命。利用可以增加APC活性和应激反应的多肽，可能有利于任何环境应激对细胞健康产生负面影响的努力。我们研究计划的长期目标是全面了解影响应激反应和细胞寿命的机制。加拿大国内的研究领域将受益于研究实验室进一步研究应激反应和细胞活力的专业知识，通过培训HQP从事学术和非学术工作。我们的研究计划将为那些适应环境压力很重要的问题提供解决方案，并最终可能转化为加拿大人和世界人民生活质量的提高。

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.