Chromosome Movement in Prometaphase

描述（申请人摘要）：本项目的目标是了解 有丝分裂染色体如何移动，它们在中期如何排列，微管如何 染色体着丝粒的附着和物理张力控制着染色体的运动， 染色体分离的时间。染色体调控缺陷 运动和分离导致染色体不稳定， 细胞分裂时的染色体。染色体不稳定性的形成 人类的配子会导致先天缺陷，如唐氏综合症。染色体 体细胞分裂的不稳定性是一个重要的因素， 癌症的恶性因子。巧合的是，染色体不稳定性也可能 对某些癌症化疗药物的有效性至关重要。 细胞分裂的重要步骤是由蛋白质的结合来调节的。 蛋白质泛素到其他蛋白质。许多参与的酶成分 已经鉴定了泛素缀合，但是通过其 它们在细胞周期中受到时间调节， 细胞的不同部分是未知的。该项目的目的是 确定这些系统的新调节蛋白，并确定时间 泛素结合机制的空间控制发生在 细胞分裂这些研究使用了分子、生物化学和 先进的显微技术来跟踪生化变化和蛋白质 泛素结合机制的相互作用，这是重要的， 哺乳动物细胞有丝分裂的调节。几种体外模型系统 使用细胞提取物、去污剂溶解的细胞或合成成分的类型， 也使用。这些模型系统部分地再现了生命中的事件 细胞，但提供了更好的机会来控制和操纵 分子环境其中一组目标旨在绘制步骤， 染色体运动本身由泛素结合控制 早期有丝分裂前中期的机械。另一组指向 了解细胞周期检查点途径的调节， 在有丝分裂中控制泛素结合以防止过早 染色体分离和染色体不稳定性。

DESCRIPTION (APPLICANT'S ABSTRACT): The goals of this project are to understand how mitotic chromosomes move, how they align at metaphase, and how microtubule attachment and physical tension at the kinetochores of chromosomes controls the timing of chromosome segregation. Defects in the regulation of chromosome movement and segregation lead to chromosome instability, the gain or loss of chromosomes during cell division. Chromosome instability in the formation of human gametes leads to birth defects such as Down's syndrome. Chromosome instability in the division of somatic cells is an important contributing factor to malignancy in cancer. Paradoxically, chromosome instability may also be critical for the effectiveness of certain drugs used in cancer chemotherapy. Important steps of cell division are regulated by the conjugation of the protein ubiquitin to other proteins. Many of the component enzymes involved in ubiquitin conjugation have been identified but the molecular pathways by which they are temporally regulated in the cell cycle or spatially regulated within different parts of the cell are unknown. The aims of this project are to identify new regulator proteins of these systems and to determine how temporal and spatial control of the ubiquitin conjugation machinery takes place within cell division. These studies use a combination of molecular, biochemical, and advanced microscopic techniques to track the biochemical changes and protein interactions of the ubiquitin conjugation machinery that are important in the regulation of mitosis in mammalian cells. In vitro model systems of several types using cell extracts, detergent-lysed cells or synthesized components are also used. These model systems partially reproduce events within the living cells but provide for better opportunities to control and manipulate the molecular environment. One set of objectives seeks to map the steps by which chromosome movements themselves are controlled by the ubiquitin conjugation machinery during prometaphase in early mitosis. Another set is pointed toward understanding the regulation of the cell cycle checkpoint pathway that functions in mitosis in controlling ubiquitin conjugation to prevent premature chromosome segregation and chromosome instability.