Aurora-A K63多聚泛素化修饰在细胞有丝分裂中的作用及机制

During cell division, cells replicate their chromatin which is then equally distributed to two daughter cells during mitosis. Defects in segregating chromatids can cause genetic instability and aneuploidy, which has been linked to tumorigenesis. To ensure proper chromatin separation, the cells employ a dynamic architecture of centrosomes, kinetochores and microtubule arrays to guide the movement of duplicated chromosomes. This process is tightly regulated by a number of protein kinases. Among them the Aurora kinases comprise an emerging family of serine/threonine protein kinases required for centrosome separation, bipolar spindle formation and cytokinesis. Mutation of Aurora kinase causes the collapse of the bipolar spindle and missegregation of chromosomes. Similarly, inhibition of Aurora kinase destabilizes the bipolar spindle. Aurora-A is localized to centrosomes and later to the poles of the bipolar spindle. Overexpression of Aurora-A can transform mouse NIH3T3 fibroblast and Rat1 cells in vitro. Moreover, expression of an Aurora-A mutant T288D, which has increased specific activity in NIH3T3 cells can form tumors in nude mice. Deregulated Aurora-A expression has been observed in various human tumors. Chromosome locus 20q13, to which Aurora-A is mapped, is also commonly amplified in various human cancers and Aurora-A amplification correlates with poor prognosis. Here, we examined Aurora-A can be ubiquitylated by lysine 63 (K63)-linked polyubiquitins during mitosis and point-mutation of the possible polyubiquitylated site gives rise to the mitosis disorder. This is the first time to demonstrate the K63-linked polyubiquitins in cell dvision, but the mechanism is still unclear.

细胞有丝分裂过程是高度复杂并且受到严格控制的，一旦发生障碍，即使是非常微小的偏差都可能导致基因组不稳定, 从而引起疾病甚至是肿瘤，而目前对细胞有丝分裂的具体分子机制还不十分明了。在细胞有丝分裂过程中，为保证姊妹染色单体和其他细胞成分能够均等地进入两个子细胞中，一系列有丝分裂激酶发挥着非常关键的作用，其中就包括Aurora-A激酶。该激酶能够促进中心体成熟、纺锤体组装，其表达或活化障碍可引起多种肿瘤发生，以其为靶点的肿瘤治疗药物已进入临床或临床前阶段，但其具体分子机制还不十分清楚。本课题组探索性实验发现Aurora-A分子可被一种新的非降解性的K63多聚泛素化修饰，且突变其修饰位点可引起非常明显的细胞有丝分裂障碍。这是首次发现有丝分裂过程中存在K63泛素修饰，因此，本项目将深入研究，为有丝分裂的分子机制及以Aurora-A为靶点的靶向肿瘤治疗提供了新的理论依据和研发思路。