The role of localisation in regulating proteolysis in mitosis

• Main Author: Cooke, F. M.
• Published: University of Cambridge 2007
• Subjects: 572.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597941

In order to maintain genetic fidelity and to avoid aberrant proliferation, the cell cycle must be carefully regulated. Progression through mitosis is controlled by ubiquitin-mediated proteolysis of cell cycle proteins, allowing each stage in the cell division process to begin only when the previous stage is successfully completed and the various checkpoints are satisfied. As proteolysis contributes to the correct timing of exit from mitosis and cytokinesis, I have investigated the mechanisms responsible for degrading specific proteins at specific times during the cell cycle and how this is regulated. By mislocalising Cdc20 substrates such as Cyclin B1 by targeting them away from the spindle, I have shown that localisation of these substrates to the mitotic spindle is a requirement for the correct timing of their degradation. When substrates are localised away from the spindle, the timing of their degradation shifts from metaphase to anaphase. I have also shown that this localised metaphase-degradation is dependent on specific regions of the mitotic spindle. Localisation to the centromeres allows substrates to be degraded at metaphase, whereas localisation to the microtubules and centrosomes prevents degradation during metaphase and results in anaphase degradation. Using a combination of live cell imaging and biochemistry, I have also investigated the mechanisms that allow global degradation during anaphase.