CENTROMERES AND CELL DIVISION CYCLE CONTROL

着丝粒和细胞分裂周期控制

• 批准号: 2459527
• 负责人: FORREST A. SPENCER
• 金额: $ 27.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2459527
• 关键词: Saccharomyces cerevisiae; cell cycle; cell cycle proteins; centromere; gene mutation; genetic transduction; in situ hybridization; molecular cloning; nucleoproteins

Because fundamental aspects of mitosis are clearly conserved in eukaryotic organisms, studies in model experimental systems are highly relevant to understanding mitotic chromosome distribution in human beings. Chromosomal aneuploidies in man are associated with prevalent disease states including malignant tumor formation, birth defects, and prenatal inviability. An understanding of the processes that normally control the transmission of euploid chromosome sets and the ordered progression of cell cycle events in eukaryotes will be essential to characterization of the defects leading to aneuploidy associated disease, with important consequences for the development of prediction and prevention measures. The distribution of a euploid chromosome set to each daughter nucleus of a mitotic division requires the execution of temporally ordered processes controlling the replication, organization, and segregation of the chromosomal DNA with its associated proteins. The fidelity of chromosome transmission depends upon the interaction of chromosomal elements (such as centromeres, origins of replication, and telomeres) with the extrachromosomal structures that participate in the complex series of ordered processes that culminate in cell division. We have recently described mitotic delays induced by the presence of mutations in kinetochore proteins or centromeric DNA in the budding yeast S. cerevisiae. Preliminary studies indicate that these delays reveal the existence of surveillance mechanism(s) monitoring kinetochore state and controlling the timing of cell cycle progression through mitosis to ensure high levels of chromosome transmission fidelity. This hypothesis will be tested in yeast using a variety of existing molecular and genetic tools, and taking advantage of mutations in centromere DNA, kinetochore protein mutants, and candidate surveillance mutants. Proteins essential for the mitotic delay(s) will be identified through the study of mutants that fail to delay in the presence of abnormal kinetochores. Further analysis of the mutants will test whether their primary defect is in the timing of chromosome segregation, and whether their normal role is extrinsic to segregation functions of the kinetochore. Detailed characterization of the delays induced by centromere DNA mutations and by kinetochore protein mutants will identify late-occurring steps in the cell cycle. Genetic interaction studies will define the number of delay phenomena under study, and will reveal the relationships between the surveillance functions disrupted in delay-deficient mutants. This work draws on the strength of budding yeast as a model eukaryote, and will form the foundation for future research in other systems on conserved processes ensuring high fidelity chromosome segregation in mitosis.

因为有丝分裂的基本方面在真核生物中是明显保守的， 生物，模型实验系统的研究与以下方面高度相关： 了解人类有丝分裂染色体的分布。染色体 人的非整倍性与流行疾病状态有关， 恶性肿瘤形成、出生缺陷和产前残疾。一个 了解通常控制疾病传播的过程 整倍体染色体组和细胞周期事件的有序进展 将是必不可少的缺陷，导致表征 与非整倍体相关的疾病， 制定预测和预防措施。 一个整倍体染色体组在每个子核中的分布 有丝分裂需要执行时间上有序的过程 控制复制、组织和隔离 染色体DNA及其相关蛋白质。染色体保真度 传播取决于染色体元件（如 着丝粒，复制起点和端粒）与 染色体外的结构，参与了一系列复杂的 以细胞分裂为顶点的有序过程。 我们最近描述了有丝分裂延迟诱导的存在， 芽殖酵母中动粒蛋白或着丝粒DNA的突变 S.啤酒。初步研究表明，这些延迟揭示了 存在监测动粒状态的监测机制， 通过有丝分裂控制细胞周期进程的时间，以确保 更高水平的染色体传递保真度。这一假设将是 使用各种现有的分子和遗传工具在酵母中进行测试， 利用着丝粒DNA的突变，动粒蛋白 突变体和候选监视突变体。蛋白质对 将通过研究突变体来确定有丝分裂延迟， 在异常的动粒出现的情况下延迟。 进一步分析 突变体将测试他们的主要缺陷是否在时间上， 染色体分离，以及它们的正常作用是否是外在的， 动粒的分离功能。详细描述了 着丝粒DNA突变和动粒蛋白诱导的延迟 突变体将识别细胞周期中晚发生的步骤。遗传 相互作用研究将定义所研究的延迟现象的数量， 并将揭示监视功能之间的关系 在延迟缺陷突变体中被破坏。这项工作利用了 芽殖酵母作为一种模式真核生物，并将形成基础， 今后在其他系统中对保守过程进行研究， 有丝分裂中染色体分离的保真度。