剪接因子SF3B6调控姐妹染色单体粘连的功能与机制研究

有丝分裂期染色体错误分离会导致非整倍体及染色体不稳定性。由黏连蛋白介导的姐妹染色单体粘连是染色体精确分离的前提。申请人以共同第一作者发表的研究工作表明，Haspin、HP1和CPC在调控姐妹染色单体粘连中发挥重要作用（Liang C et al., EMBO Rep, 2018; Yi Q et al., EMBO Rep, 2018; Yi Q et al., J Biol Chem, 2019）。Sororin作为黏连蛋白的重要调节亚基，促进姐妹染色单体粘连的建立和维持，然而其调控机制仍不清楚。本项目中将以申请人初步鉴定的Sororin与剪接因子SF3B6的直接结合为基础，解析Sororin与SF3B6相互作用的分子基础及其在有丝分裂中的功能，阐明SF3B6调节姐妹染色单体粘连的分子机制。项目的顺利完成，将揭示调控染色体精确分离的新机制，为有丝分裂靶向的抗癌治疗提供新思路。

Errors during mitotic chromosome segregation may lead to aneuploidy and chromosomal instability. Sister chromatid cohesion mediated by the cohesin complex is a prerequisite for precise chromosome segregation. The applicant’s previously published work has shown that Haspin, HP1 and the chromosomal passenger complex (CPC) play an important role in the regulation of sister chromatid cohesion during mitosis (Liang C et al., EMBO Rep, 2018; Yi Q et al., EMBO Rep, 2018; Yi Q et al., J Biol Chem, 2019). As an important regulatory subunit of cohesin, Sororin promotes the establishment and maintenance of sister chromatid cohesion. However, the molecular mechanism underlying the regulation of Sororin function in sister chromatid cohesion is poorly understood. Based on the applicant’s preliminary finding of the direct interaction between Sororin and the splicing factor SF3B6, this project aims to dissect the molecular basis and functional significance for the Sororin-SF3B6 interaction, and elucidate the molecular mechanism underlying the role for SF3B6 in regulating sister chromatid cohesion. Successful completion of this project will reveal the mechanism by which SF3B6 ensures precise chromosome segregation, and provide new strategies for anti-mitotic cancer therapy.