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Title: Regulation of mitotic exit and cytokinesis in Saccharomyces cerevisiae
Author: Lee, Sarah Elizabeth
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2001
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Cell proliferation depends upon the duplication of chromosomes and the segregation of duplicated sister chromatids to opposite poles of the cell prior to cell division (cytokinesis). Each of these processes must occur with high fidelity and in a strict order to ensure that the cell's genetic material is transferred to its progeny. Genetic instability resulting from aberrant cell division is implicated in tumour progression in multicellular organisms. Much of our understanding of eukaryotic cell cycle control has been gained by studying model systems such as the budding yeast, Saccharomyces cerevisiae. Major cell cycle regulatory points are referred to as transitions and include START, which marks commitment to the entire cell cycle. Another occurs at M/G1, when cells undergo mitotic exit and cytokinesis. Mitotic exit requires destruction of mitotic cyclin-dependent kinase (CDK) activity (Cdc28-C1b in budding yeast) and is controlled by the mitotic exit network (MEN). Although many components of this protein network have been identified, including the G-protein Tem1, the kinases Cdc15, Dbf2 and Cdc5, the phosphatase Cdc14, and Mob1, until recently their regulation was poorly understood. I have investigated the order of function of the MEN and found that it forms a signal transduction cascade which functions in the order Tem1-Cdcl5-Mob1-Dbf2-Cdc14. The polo-like kinase Cdc5 serves as both a negative and positive regulator of the MEN. MEN activation is necessary and sufficient for formation of the actomyosin contractile ring which is required for cytokinesis, and for CDK inactivation. Completion of cytokinesis requires an additional step, which may involve relocalisation of the MEN proteins to the bud neck. Control of MEN activation operates through Tem1, and is mediated in part by Bub2 and Bfa1. Bub2 and Bfa1 were identified as components of a branch of the spindle assembly checkpoint (SAC) pathway, and are thought to form a 2-component GTPase activating protein (GAP) for Tem1. Consistent with this, Bub2 and Bfa1 both negatively regulate and form a complex with Tem1. To understand how they control the MEN, I have studied the regulation of Bub2 and Bfa1. Phosphorylation of Bfa1 by two cell cycle-regulated kinases, Cdc28 and Cdc5, is likely to activate Bub2/Bfa1 GAP activity. Rather than being a branch of the SAC, Bub2/Bfa1 appear to function during a variety of mitotic arrests, forming a "spindle positioning checkpoint", which couples spindle elongation through the bud neck to initiation of mitotic exit and cytokinesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available