Mechanisms underlying chromosome segregation

染色体分离的机制

• 批准号: 10625226
• 负责人: Susan Biggins
• 金额: $ 35.2万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625226
• 关键词: Aneuploidy; Biochemical; Cell Cycle; Cell Cycle Regulation; Cell division; Cells; Centromere; Chromosome Segregation; Chromosome abnormality; Chromosomes; Congenital Abnormality; Cytology; Defect; Development; Disease; Ensure; Eukaryota; Evolution; Genetic; Genome Stability; Human; Inherited; Kinetochores; Lead; Malignant Neoplasms; Microtubules; Organism; Process; Proteins; Saccharomycetales; Spontaneous abortion; Time; Weight-Bearing state; Work; Yeasts; cancer cell; daughter cell; human disease; in vitro Assay; prevent

Project Summary Accurate cell division is essential for the development of all organisms. During each cell cycle, chromosomes must be precisely partitioned to daughter cells. Defects in chromosome partitioning generate aneuploidy, the state where entire chromosomes are gained or loss. Aneuploidy is a the most common chromosomal abnormality in cancer cells and is thought to be a major factor in the evolution of cancer. It is also the leading cause of miscarriages and hereditary birth defects in humans. The proposed work will lead to an understanding of the mechanisms that ensure accurate chromosome partitioning. This work is important for maintaining genomic stability and preventing human disease. Chromosome partitioning occurs when spindle microtubules move chromosomes by interacting with kinetochores, the machines that assemble onto the chromosome at a locus called the centromere. Kinetochores carry out a number of functions, such as maintaining load-bearing attachments to the ends of microtubules that are continually growing and shrinking. They also control the cell cycle when there is a defect in kinetochore attachments to microtubules. Our lab will address two fundamental questions about chromosome segregation using in vitro assays: 1) How is kinetochore assembly regulated? 2) How do kinetochore proteins contribute to force-dependent kinetochore-microtubule attachments? We will use budding yeast for these studies because they are amenable to biochemical, genetic and cytological studies, and the yeast kinetochore is the best characterized to date. Taken together, our work will lead toward an understanding of the fundamental mechanisms of chromosome partitioning in all eukaryotes.

项目摘要 准确的细胞分裂对所有生物的发育都是必不可少的。在每个细胞周期中， 必须精确地分配给子细胞。染色体分配的缺陷产生非整倍性， 整个染色体获得或丢失的状态。非整倍体是最常见的染色体异常 在癌细胞中，它被认为是癌症演变的主要因素。这也是导致 流产和遗传性先天缺陷。拟议的工作将有助于了解 确保染色体精确分配的机制。这项工作对于维持基因组 稳定性和预防人类疾病。当纺锤体微管移动时， 染色体通过与着丝粒相互作用，组装到染色体上的一个位点上的机器 称为着丝粒。动粒执行许多功能，例如保持承重 微管末端的附着物不断生长和收缩。它们还控制着细胞 当着丝粒与微管的连接有缺陷时，会出现一个周期。我们的实验室将解决两个基本问题 关于使用体外分析的染色体分离的问题：1）动粒组装是如何调节的？（二） 动粒蛋白如何促成力依赖性的动粒-微管附着？我们将使用 芽殖酵母用于这些研究，因为它们适合于生物化学、遗传学和细胞学研究， 酵母动粒是迄今为止表征最好的。总之，我们的工作将导致一个 了解所有真核生物中染色体分配的基本机制。