Coupling of Protein Synthesis with Cell Division

蛋白质合成与细胞分裂的耦合

• 批准号: 9290853
• 负责人: Rodolfo Aramayo
• 金额: $ 34.55万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-26 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9290853
• 关键词: Affect; Aging; Biochemical; Biological Assay; Biological Models; Cell Aging; Cell Count; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cell Size; Cell division; Cell physiology; Cells; Cellular Membrane; Chromosome Segregation; Coupling; Data; Disease; Dreams; Elements; Enzymes; Genetic; Glucose; Goals; Growth; Homeostasis; Intervention; Knowledge; Lead; Light; Link; Lipids; Longevity; Mass Spectrum Analysis; Measures; Messenger RNA; Methodology; Mission; Mitosis; Molecular; Mutation; Nuclear Envelope; Nutrient; Periodicity; Phenotype; Physiological; Play; Population; Process; Production; Proliferating; Property; Protein Biosynthesis; Proteins; Public Health; Reporting; Ribosomal Proteins; Ribosomes; Role; Saccharomycetales; Series; Testing; Time; Transcript; Translating; Translation Process; Translations; United States National Institutes of Health; Yeasts; cell growth; dietary restriction; experimental study; gene therapy; grasp; lipid biosynthesis; mutant; novel therapeutic intervention; paralogous gene; ribosome profiling; spindle pole body

Protein synthesis governs if, how fast, and how many times cells divide. Yet how protein synthesis is linked molecularly with cell division is unknown. We use budding yeast as a model system to answer this problem. Because yeast has unique properties, suited for genetic and biochemical experiments. New methodologies can identify transcripts that engage with the protein synthesis machinery, the ribosomes, in the process of translation. For the first time in the field, we applied this ribosome profiling methodology in synchronously dividing cells that maintained the physiological coupling of protein synthesis with their division. In this collaborative proposal, we will leverage these findings to tackle the long-standing problem of protein synthesis requirements for cell divisions. In Aim 1, we will determine how translational control of lipogenic enzymes regulates the remodeling of cellular membranes during cell division. Furthermore, we will determine how protein synthesis adjusts the production of proteins that trigger duplication of the spindle pole body, an essential part of the machinery of chromosome segregation. We will also identify translationally regulated mRNAs under dietary restriction, which changes the size of cells and increases the number of times cells divide before they die. In Aim 2, we will extend ribosome profiling to settings of specific ribosomal protein mutants that delay cell division and increase lifespan. These genetic interventions will enable us to identify mRNA targets of translational control that underpin cell division and replicative longevity when protein synthesis is limited. Knowing how translational control affects the timing and number of cell divisions will reveal fundamental links between cell growth, protein synthesis, cell division and aging, enabling novel therapeutic interventions in proliferative diseases.

蛋白质的合成决定了细胞是否分裂，分裂的速度和次数。然而蛋白质合成是如何 与细胞分裂的分子联系是未知的。我们使用芽殖酵母作为模型系统来回答这个问题 问题.由于酵母具有独特的性质，适合于遗传和生化实验。新 方法学可以鉴定与蛋白质合成机器，核糖体， 在翻译的过程中。在该领域，我们首次应用这种核糖体分析方法， 在同步分裂的细胞中，保持蛋白质合成与它们的 师.在这项合作建议中，我们将利用这些发现来解决长期存在的问题 细胞分裂所需的蛋白质合成。在目标1中，我们将确定翻译控制 脂肪生成酶的调节细胞分裂过程中细胞膜的重塑。此外，委员会认为， 我们将确定蛋白质合成是如何调节蛋白质的产生的，这些蛋白质触发了细胞的复制。 纺锤体极体是染色体分离机制的重要组成部分。我们还将确定 在饮食限制下，调节的mRNA改变了细胞的大小， 细胞死亡前分裂的次数在目标2中，我们将核糖体分析扩展到 特异性核糖体蛋白突变体，延迟细胞分裂并延长寿命。这些遗传 干预将使我们能够确定支持细胞分裂的翻译控制mRNA靶点 以及蛋白质合成受限时的复制寿命。了解翻译控制如何影响 细胞分裂的时间和数量将揭示细胞生长，蛋白质合成， 细胞分裂和老化，使新的治疗干预增殖性疾病。