包含在染色体中的父代遗传信息通过纺锤体丝与染色体着丝粒的协同作用来完成有丝分裂。着丝粒是调控真核细胞有丝分裂染色体稳定性与细胞质量控制的重要蛋白质机器，其动态组装与可塑性调控异常促进肿瘤的发生与发展。TIP60是一个调控真核细胞基因组稳定性的重要乙酰转移酶，但其如何维系真核细胞有丝分裂染色体稳定性尚不清楚。我们最新研究鉴定了调控真核细胞染色体稳定性的CDK1-TIP60-Aurora B信号轴(Nat. Chem. Biol.), 但是我们仍不清楚TIP60的详尽信号转导通路以及TIP60如何调控着丝粒功能可塑性。为此，我们拟解析TIP60如何与Aurora B协同调节染色体的正确连接、鉴定TIP60信号通路调节着丝粒功能可塑性所涉及的重要效应分子、描绘TIP60介导乙酰化调控着丝粒功能可塑性的分子动力学特征。本项目的实施将阐明TIP60乙酰转移酶调控着丝粒功能可塑性的动态分子机制。

Accurate segregation of chromosomes in mammalian cells requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Kinetochore is a super-macromolecular structure located to centromeres of the chromosome. The essential function of kinetochore is to orchestrate accurate interactions between chromosomes and spindle microtubules and serve as a quality control device to determine the time for sister chromatid separation. As an important acetyltransferase in maintenance of chromosome stability, how TIP60 functions at the centromere was regulated and whether it also guides chromosome dynamics and stability during mitosis have been outstanding questions. Recently, we have identified a signaling axis in which Aurora B activity is modulated by CDK1–cyclin B via the acetyltransferase TIP60 in human cell division (Nat. Chem. Biol.). However, the detailed signaling pathway of TIP60 involved in the control of centromere plasticity still remains elusive. Therefore, further elaboration of coordination between TIP60 and Aurora B in proper chromosome attachment, identification of effectors involved in the control of centromere plasticity and delineation of molecular dynamics by TIP60-mediated acetylation in centromere plasticity will provide new insight into the relationship between cell cycle progression with genomic stability.