The mechanisms of how sister chromatid separation is regulated in mitosis
Description
Faithful chromosome segregation in mitosis is required for maintaining chromosome stability, thus ensuring the accurate propagation of genetic information. Multiple mitotic pathways have evolved to regulate this process including kinetochore-microtubule (KT-MT) attachment and centromeric cohesion. My studies focus on the regulation of KT-MT attachment and centromeric cohesion. The kinetochore is a multi-protein complex that serves as spindle-microtubule binding sites for chromosome segregation. The spindle kinetochore assembly complex (Ska) is required for proper KT-MT attachment, but the underlying mechanisms are unknown. I demonstrate that multisite phosphorylation of Ska by Cdk1 enables Ska binding to Ndc80C and recruits Ska to the outer kinetochore to promote chromosome segregation. Duplicated sister chromatids are linked by the cohesin complex which is termed cohesion. Proper regulation of centromeric cohesion is essential for chromosome segregation. Cyclin-dependent-kinase (Cdk) 11 has been shown to promote centromeric cohesion. My results demonstrate that Cdk11 localizes to centromeres and binds to RNA polymerase (RNAP) II. Cdk11 depletion significantly decreases RNAPII levels at centromeres and centromeric transcription. As centromeric transcription is essential for centromeric cohesion, I propose that Cdk11 binds to and phosphorylates RNAPII to enhance centromeric transcription, thus promoting centromeric cohesion. All the above results reveal the critical mechanisms underlying chromosome segregation. As chromosome missegregation drives aneuploidy that promotes tumorigenesis, these mechanisms may provide potential therapeutic targets for cancer.