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

使用与后期促进复合物相互作用的小肽来表征控制芽殖酵母寿命的分子机制

• 批准号: RGPIN-2017-05478
• 负责人: Harkness, Troy
• 金额: $ 4.37万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=690911
• 关键词: Characterization; molecular; mechanisms; governing; budding

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.

有证据表明，细胞寿命与其损伤修复能力相关。从酵母到果蝇，模型生物中的遗传筛选一直证明，参与压力反应网络的基因在寿命测定中起着决定性的作用。使用酿造酵母模型系统，我们表明调节的细胞周期进程与应力反应和正常寿命紧密相关。我们表征了酵母中的后期促进复合物（APC）的工作，酵母是一种大型高度保守的蛋白质络合物，用于将底物靶向泛素依赖性降解所需的蛋白质，它描述了APC的许多新作用和底物。 APC在很大程度上靶向抑制有丝分裂进展和G1维持降解的蛋白质。在过去的15年中，我们的许多NSERC资助的研究表明，APC也需要有丝分裂组蛋白沉积和翻译后修饰，压力反应，基因组稳定性和寿命。因此，我们的工作表明，APC在维持细胞活力和最终寿命方面起着核心和关键作用，导致假设增加APC活性会增加细胞应激反应和寿命。此处描述的研究计划将着重于隔离与APC复合物结合或影响APC功能的因素，以增加压力反应，细胞活力和寿命增加的小肽。我们已经进行了遗传筛选以隔离这些小肽，并将集中在下一个资金期间的表征上。这项工作很重要，因为我们目前没有操纵细胞应激反应机制以增加细胞活力和寿命的方法。利用可能增加APC活性和压力反应的肽可能会受益于环境应力对细胞健康的负面影响的任何努力。我们的研究计划的长期目标是对影响压力反应和细胞寿命的机制进行全面了解。加拿大境内的研究领域将通过在研究压力反应和细胞活力的研究实验室的进一步专业知识中受益，并通过培训HQP从事学术和非学术工作。我们的研究计划将为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的生活质量。