Mechanisms underlying chromosome segregation

项目摘要 准确的细胞分裂对所有生物体的发育都是至关重要的。在每个细胞周期中，染色体 必须精确地分割成子代细胞。染色体分割的缺陷会产生非整倍体， 整个染色体获得或丢失的状态。非整倍体是一种最常见的染色体异常 在癌细胞中，被认为是癌症进化的主要因素。它也是导致 人类的流产和遗传性出生缺陷。拟议的工作将导致对 确保准确的染色体分割的机制。这项工作对维持基因组具有重要意义。 稳定和预防人类疾病。染色体分裂发生在纺锤体微管移动时 染色体通过与动粒相互作用，动粒是在某个位置组装到染色体上的机器 被称为着丝粒。运动中枢执行许多功能，例如维持承重 附着在不断生长和缩小的微管末端。它们还控制着细胞 微管上的动粒附着体存在缺陷时的周期。我们的实验室将解决两个基本问题 关于体外染色体分离的问题：1)着丝粒组装是如何调节的？2) 动粒蛋白如何促进力依赖的动粒-微管连接？我们将使用 用于这些研究的萌芽酵母，因为它们适合进行生化、遗传和细胞学研究，以及 酵母着丝点是迄今为止最好的特征。总而言之，我们的工作将导致 了解所有真核生物中染色体分裂的基本机制。

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.