Regulation of Chromosome Segregation

准确的细胞分裂取决于正确的染色体分离成子细胞。染色体分离缺陷导致遗传不稳定和非整倍体，癌症和出生缺陷的标志。染色体通过着丝点分离，着丝点是一种特殊的蛋白质结构，它被组装在着丝粒DNA序列上，并介导着丝分裂纺锤体的附着。虽然许多着丝点成分已被确定，但不清楚着丝点是如何调节来介导染色体分离的。本项目的长期目标是利用出芽酵母为模型系统，阐明着丝点功能和染色体分离的调控和机制。着丝粒功能的关键调节因子是保守的Ip11/aurora2蛋白激酶。由于酵母Ip11p激酶的缺陷导致非整倍体，而人类aurora2激酶是一种致癌基因，因此对该激酶的研究对于理解染色体分离和细胞转化都很重要。该建议将重点放在Ip11/aurora2激酶和另一个保守的着丝粒组分，组蛋白H3变体Cse4p上，作为阐明染色体分离机制的一种手段。具体目标包括：1)分析Ip11p和Cse4p组装成着丝点，以了解着丝点组装的机制；2)研究Ip11p激酶的调控和底物，以了解它如何调节染色体分离；3)研究Ip11p在纺锤体检查点中的作用；4)研究Ip11p和Cse4p蛋白的着丝点功能，以了解着丝点是如何被调节的。这些研究将有助于更好地理解染色体分离的机制和Ip11/aurora2激酶在基因组稳定性中的作用，研究可能阐明癌症产生的细节，并为治疗提供新的途径。

Accurate cell division depends upon proper chromosome segregation into daughter cells. Defects in chromosome segregation lead to genetic instability and aneuploidy, hallmarkers of cancer and birth defects. Chromosomes segregate using their kinetochores, the specialized protein structures that are assembled on centromeric DNA sequences and mediate attachment to the mitotic spindle. Although many kinetochore components have been identified, it is unknown how kinetochores are regulated to mediate chromosome segregation. The long-term goal of this project is to elucidate the regulation and mechanisms of kinetochore function and chromosome segregation using the budding yeast Saccharomyces cerevisiae is a model system. A key regulator of kinetochore function is the conserved Ip11/aurora2 protein kinase. Since defects on the yeast Ip11p kinase lead to aneuploidy and the human aurora2 kinase is an oncogene, studies on the kinase are important to understanding both chromosome segregation and cellular transformation. This proposal This proposal focuses on the Ip11/aurora2 kinase and another conserved kinetochore component, the histone H3 variant Cse4p, as a means toward elucidating the mechanisms of chromosome segregation. The specific aims include: 1) analyzing Ip11p and Cse4p assembly into kinetochores to gain insight into mechanisms of kinetochore assembly, 2) investigating the regulation and substrates of the Ip11p kinase to understand how it regulates chromosome segregation, 3) examining the role of Ip11p in the spindle checkpoint, and 4) investigating the kinetochore functions of the Ip11p and Cse4p proteins to understand how kinetochores are regulated. These studies will lead to a better understanding of the mechanisms of chromosome segregation and the role of the Ip11/aurora2 kinase in genomic stability, studies may elucidate details about the generation of cancer and provide new avenues for therapy.