Cell Cycle Regulation In Budding Yeast

出芽酵母的细胞周期调控

• 批准号: 7967647
• 负责人: Orna Cohen-Fix
• 金额: $ 27.35万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7967647
• 关键词: Affect; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cells; Chromosome Segregation; Code; Complement; Complex; Defect; Endoplasmic Reticulum; Gene Proteins; Genes; Genetic; Goals; Kinetochores; Lead; Link; Membrane; Membrane Proteins; Mitosis; Mitotic; Molecular; Monitor; Mutation; Nuclear Envelope; Pathway interactions; Phenotype; Process; Proteins; Regulation; Research Priority; Role; Saccharomycetales; Sarin; cdc Genes; novel; protein function; repaired

Chromosome segregation is a complex process that requires multiple levels of regulation. Our goal is to understand the regulation of various mitotic processes and to uncover the molecular function of proteins that have been identified as mitotic regulators but whose exact role is unknown. In the past year, we studied the protein Apq12, a novel protein involved in cell cycle regulation. Cells have regulatory mechanisms, called checkpoints, that monitor the presence of intracellular damage or structural errors, and arrest cell cycle progression until the damage or error is repaired. Consequently, mutations in various cell cycle genes do not lead to a detectable phenotype because checkpoint pathways compensate for defects that would otherwise be deleterious. To uncover novel cell cycle genes, we previously conducted a screen for mutations that lead to cell death when checkpoint pathways were inactive (Sarin et al, Genetics 2004). Through this screen we isolated APQ12, a gene that codes for an ER-associated protein of unknown function. The involvement of an ER protein in cell cycle regulation is intriguing, as this is one of the first examples that links ER function with cell cycle progression. Interestingly, the absence of Apq12 leads to intracellular damage that activated the spindle assembly checkpoint pathway, suggesting that Apq12 is involved in spindle or kinetochore function. We have been able to discern the orientation of Apq12 within the ER membrane and we are in the process of isolating Apq12- interacting proteins. Furthermore, we have identified several genes whose over-expression suppresses the lethality associated with the absence of both Apq12 and a functional spindle assembly checkpoint pathway. We are currently focusing our efforts on understanding the mechanism by which these genes promote viability and on the molecular function of Apq12. Note: due to changes in research priorities this project is temporarily suspended.

染色体分离是一个复杂的过程，需要多层次的调控。我们的目标是了解各种有丝分裂过程的调节，并揭示已被确定为有丝分裂调节剂但其确切作用尚不清楚的蛋白质的分子功能。 去年，我们研究了Apq12蛋白，这是一种参与细胞周期调控的新型蛋白。 细胞具有称为检查点的调节机制，可以监测细胞内损伤或结构错误的存在，并阻止细胞周期的进展，直到损伤或错误得到修复。因此，各种细胞周期基因的突变不会导致可检测的表型，因为检查点途径补偿了原本有害的缺陷。为了发现新的细胞周期基因，我们之前对检查点途径不活跃时导致细胞死亡的突变进行了筛选（Sarin 等人，Genetics 2004）。 通过这个筛选，我们分离出了 APQ12，这是一种编码功能未知的 ER 相关蛋白的基因。 ER 蛋白参与细胞周期调节是很有趣的，因为这是将 ER 功能与细胞周期进展联系起来的第一个例子。有趣的是，Apq12 的缺失会导致细胞内损伤，从而激活纺锤体组装检查点通路，这表明 Apq12 参与纺锤体或着丝粒功能。我们已经能够辨别 Apq12 在 ER 膜内的方向，并且我们正在分离 Apq12 相互作用蛋白。此外，我们还发现了一些基因，它们的过度表达会抑制与 Apq12 和功能性纺锤体组装检查点通路缺失相关的致死率。我们目前的重点是了解这些基因促进活力的机制以及 Apq12 的分子功能。 注：由于研究重点发生变化，该项目暂时停止。