Kinetochore Spindle Interaction in Fission Yeast

描述（由申请人提供）：有丝分裂中染色体的均等分离需要染色体和有丝分裂纺锤体之间的适当相互作用。着丝点是组装在着丝粒dna上的特殊结构，并介导染色体与纺锤体微管之间的连接。各种生物体的着丝点在结构上有很大的不同，但其功能却基本相似。对酿酒葡萄球菌的着丝点已经有了很多了解。然而，目前尚不清楚我们在多大程度上可以将这种简单点着丝点的知识应用于复杂的区域着丝点，如人类的着丝点。本研究的长期目标是将S. pombe的着丝点结构作为区域着丝点的模型，并了解着丝点如何与纺锤体协调，以确保这种模式生物中染色体分离的高保真度。通过对s.p ombe, s.c reevisiae和其他生物的着丝点的比较和对比，我们希望描绘出着丝点功能的一般生物学原理。这些知识将有助于识别肿瘤细胞中的分子病变，这些病变导致非整倍体的高发生率-几乎在所有类型的肿瘤中都检测到错误的染色体数目。本文提出了分析分裂酵母中着丝点/纺锤体相互作用的三个具体目标：

DESCRIPTION (provided by applicant): Equal chromosome segregation in mitosis requires proper interaction between the chromosomes and the mitotic spindle. Kinetochores are the specialized structures that are assembled on centromeric DNAs and mediate the attachment between the chromosomes and the spindle microtubules. Kinetochores of various organisms differ remarkably in their architectures and yet perform fundamentally similar functions. Much has been learnt of the kinetochores in S. cerevisiae. However, it is unclear to what extent can we apply the knowledge of this simple point kinetochore onto complex regional kinetochores such as those of humans. The long-term goal of this proposal is to dissect the kinetochore structure in S. pombe as a model of the regional kinetochores and to understand how kinetochores co-ordinate with the spindle to ensure the high fidelity of chromosome segregation in this model organism. By comparing and contrasting the kinetochores of S. pombe, S. cerevisiae and those of other organisms, we wish to delineate the general biological principles of the kinetochore functions. This knowledge will facilitate the identification of the molecular lesions in tumor cells which lead to high rate of aneuploidy - erroneous chromosome numbers that are detected in virtually all types of tumor. Three specific aims are proposed here to analyze the kinetochore/spindle interaction in fission yeast: 1. To identify novel kinetochore and spindle components in fission yeast that are required for their proper attachment. 2. To characterize the architectural and functional roles of novel kinetochore proteins. 3. To explore the mechanism of how kinetochores switch from a static affinity to spindle pole to a dynamic affinity to spindle MTs at the entry of mitosis.