组蛋白H3变体Cse4在着丝粒的精确定位对维持基因组稳定性的分子机制研究

项目名称： 组蛋白H3变体Cse4在着丝粒的精确定位对维持基因组稳定性的分子机制研究

项目编号： No.31271365

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 万亚坤

作者单位： 中国科学院上海药物研究所

项目金额： 80万元

中文摘要： 动点-微管相互作用介导的有丝分裂能有效地维持基因组的稳定性。基因组的不稳定性与染色体的分离异常往往被认为是癌症发生的标志性事件。真核生物中以CENP-A为核心的动点组装途径多年来一直是生物学家研究的热点。CENP-A在多种肿瘤组织中高表达，已证实CENP-A的表达异常与肿瘤细胞增殖以及基因组的不稳定性密切相关。本课题组前期结果发现酵母细胞过度表达的Cse4（CENP-A同源基因）在细胞核中弥散分布并错误地结合到常染色质部分，导致染色体分离异常，细胞生长明显受到抑制。CENP-A高表达如何破坏了基因组遗传稳定性，及与其相关的水解机制，都是科学家们亟待解决的问题。本项目将重点研究Cse4在着丝粒精确定位的作用机制、鉴定参与水解过度表达Cse4的调节因子。通过对Cse4的精确定位及其水解调控机理的深入研究，为今后开展非整倍体相关疾病的预防、检测等提供重要的科学依据与理论支持。

中文关键词： Cse4；基因组稳定性；精确定位；；

英文摘要： Chromosome segregation is mediated by the interaction between microtubules and kinetochores. The maintenance of chromosome number during mitosis is important for genome stability. Genome instability and the defect on chromosome segregation have been linked to cancer. Kinetochore assembly is initiated by recruitment of CENP-A to centromeric DNA. Several studies have demonstrated that abnormal expression of CENP-A is involved in tumorigenesis and genome instability. Our primimary studies have showed that overexpressed Cse4 dispersly distrubited in the nucleus, which lead to the defect of chromosome segregation and slow growth in budding yeast. It is largely unknown how the overexpressed CENP-A can disrupt the genome stability and what kind of regulators are involved in its proteolysis pathway. In this proposal, we intend to elucidate the molecular mechanism of the precise localization of CENP-A , identify and characterize the key regulatory factors involved in its proteolysis. These studies will be important for understanding how chromosomes are equally segregated and provide great insights on how genome instability may cause human diseases.

英文关键词： Cse4；Genome stability；Precise incorporation；；