Regulation of Chromosome Segregation

 描述(申请人提供)：所有生物体的产生和生存依赖于细胞分裂的忠实执行。对监管和控制的全面了解 细胞过度分裂对于阐明控制自我更新、增殖和发育的机制至关重要。细胞周期中的一个关键事件是将每对复制的染色体精确地分割成子细胞。分离的缺陷会导致非整倍体，即整个染色体获得或丢失的状态。非整倍体是大多数肿瘤细胞的标志，并被认为是癌症进化的主要因素。它也是人类自发流产和遗传性出生缺陷的主要原因。这项拟议的工作将导致对确保准确的染色体分离从而保持基因组稳定和预防人类疾病的机制的理解。染色体分离需要纺锤体微管产生的力，这些力通过与着丝粒相互作用转化为染色体运动，着丝点是组装在着丝粒染色质上的高度保守的结构。准确的分离需要动轴来保持与不断生长和收缩的微管末端的承重连接。动点还必须从相反的两极生物定向并附着到微管上。当双向存在缺陷时，纠错系统会破坏不正确的附着体的稳定性。在下一个供资期间，这项提案将处理外地的未决问题 关于动粒-微管附着的中介机制和对动粒双向的调节。总之，这些研究将成为了解所有真核生物中分离的基本机制的一种手段。

 DESCRIPTION (provided by applicant): The generation and survival of all organisms depends on the faithful execution of cell division. A complete understanding of the regulation and controls over cell division is critical to elucidate the mechanisms that govern self-renewal, proliferation and development. A key event in the cell cycle is the precise partitioning of every pair of duplicated chromosomes to daughter cells. Defects in segregation lead to aneuploidy, the state where entire chromosomes are gained or loss. Aneuploidy is a hallmark of most tumor cells and has been postulated to be a major factor in the evolution of cancer. It is also the leading cause of spontaneous miscarriages and hereditary birth defects in humans. The proposed work will lead to an understanding of the mechanisms that ensure accurate chromosome segregation and thus maintain genomic stability and prevent human disease. Chromosome segregation requires forces generated by spindle microtubules that are translated into chromosome movement through interactions with kinetochores, the highly conserved structures that assemble onto centromeric chromatin. Accurate segregation requires kinetochores to maintain load- bearing attachments to the ends of microtubules that are continually growing and shrinking. Kinetochores must also biorient and attach to microtubules from opposite poles. When there is a defect in biorientation, error correction systems destabilize improper attachments. In the next funding period, this proposal will address outstanding issues in the field about the mechanisms that mediate kinetochore-microtubule attachment and the regulation over kinetochore biorientation. Together, these studies will be a means toward understanding the fundamental mechanisms of segregation in all eukaryotes.