Role of the central kinetochore in chromosome segregation

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The transmission of genetic information during cell division requires the coordination of three critical events; first, the attachment of chromosomes to the microtubules of the mitotic spindle, second the application of forces that pull chromosomes towards the poles of the cell and away from spindle mid-zone and third, the coordination of completion of these events with the onset of cytokinesis. The kinetochore is a complex structure of proteins that is associated with the centromeres of chromosomes. While the structure and organization of the centromere and kinetochore is diverse among eukaryotes, they play an evolutionarily conserved and central role in attaching chromosomes to microtubules in all cell types. Chromosome attachment, or bi-orientation, is an error prone process. The kinetochore is not only required to segregate the chromosomes, but also to report the status of attachment. Bi-orientation of all the chromosomes results in tension on the spindle, and is required for entry into anaphase. Defects in bi-orientation result in lack of tension on the spindle, and are reported locally; a defect at one chromosome is sufficient to trigger a) the repair of defective attachments, and if repair is incomplete b) activation of a cell cycle checkpoint that delays entry into anaphase. The mechanism of repair, and the requirement for the kinetochore for in checkpoint activation is well established. Once the checkpoint is activated, the cell cycle delay must be maintained until all attachments have been repaired. In the last several years, proteins of the central kinetochore (CK) have emerged as candidates for coordinating repair with checkpoint control. However, the mechanism by which repair and checkpoint functions are coupled is less understood. The goal of this project is to understand how the repair and checkpoint functions of CK proteins are controlled in cells.