纺锤体组装检验点因子BubR1的结构与功能研究

During cell division, the spindle assembly checkpoint (SAC) ensures the high fidelity of sister chromatids segregation and determines whether the cell cycle enters to prophase. BubR1 is a key component of SAC, it forms part of the mitotic checkpoint complex that also contains Bub3, MAD2 and Cdc20, which inhibits sister chromatids segregation and prophase I initiation.Three main regions can be identified in BubR1: the N-terminal region contains the kinetochore localization domain; the intermediate region is required for Bub3 binding; and the C-terminal region contains a catalytic serine/threonine kinase domain. The BubR1 homolog Mad3 lacks the C-terminal domain. However, there are no known species with both BubR1 and MAD3. BubR1 is only identified in higher eukaryotes, whereas MAD3 is found in yeasts, worms and plants. This difference implies that BubR1 has been acquired additional functions during evolution for which thr the kinase is required. There are great debates on BubR1 and the significance of its kinase activity to the checkpoint, mostly because there is no known substrate of BubR1 until now. In addition, besides the role in SAC, mutant of BubR1 is also related to genome chromosome stability and carcinogenesis. Therefore, the functional and atomic structural study will provide molecular insight into the mechanism of BubR1 in SAC, and carcinogenesis as well as its evolutionary relationship with other homologues.

细胞分裂中，为保证染色体分离的忠实性，纺锤体组装检验点负责监控和调节有丝分裂是否由中期进入后期。BubR1是有丝分裂纺锤体组装检验点的关键组分之一，能够与检验点的其它组分一起形成有丝分裂检验点复合物，防止姐妹染色单体分离，抑制后期的起始。BubR1的N端动粒定位区和中间Bub3结合区与另一有丝分裂检验点因子Mad3高度同源，C端为丝/苏氨酸激酶区。但BubR1仅存在于哺乳动物中；而Mad3仅存在于酵母、植物及昆虫细胞中，且其不具有激酶区。推测BubR1可能在进化过程中获得了新结构域和新功能。迄今为止尚未在体内找到其激酶区直接作用的底物,BubR1在检验点中的作用也存在很大争议。BubR1突变还会导致染色体不稳定以及癌症的发生。因此，更深入研究BubR1结构与功能的关系，将有益于进一步了解其在有丝分裂检验点、肿瘤发生中的作用机制和该基因的进化关系，并为设计小分子抑制剂提供基础。