Study of the mechanisms in the regulation of centromere-kinetochore network
Description
Accurate chromosome segregation during mitosis is faithful for transmission of the genome from one generation to another. Chromosome missegregation causes genomic instability, which further leads to aneuploidy, a hallmark of cancer. Kinetochore-microtubule interactions and centromeric transcription are the two major mechanisms ensuring accurate chromosome segregation. However, these important mechanisms are not well understood. In this thesis, I focus on understanding them. Using in vitro binding assay, I found that Cyclin-dependent kinase 1 (Cdk1) phosphorylates an essential outer kinetochore complex Ska, which promotes its binding to the kinetochore and is essential for mitotic progression. These important findings reveal a critical mechanism controlling kinetochore-microtubule interactions. In addition, I attacked another important question of how centromeric transcription is regulated. By manipulating centromeric transcription using a novel approach, I demonstrated that centromeric transcription is required for centromeric cohesion protection. I also found that an important epigenetic mark H3K4 di-methylation on centromeric chromatin is cell-cycle regulated as well as regulated by mitotic kinase Bub1. As chromosome missegregation-induced aneuploidy promotes tumorigenesis, my findings here might also provide potential therapeutic targets for human malignancies.