Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.756343
Title: Quantitative biology of cell cycle decision making
Author: Patterson, James Oliver
ISNI:       0000 0004 7429 2966
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Abstract:
In the fission yeast Schizosaccharomyces pombe as well as metazoans, the G1/S and G2/M transitions are a focal point of cell cycle regulation. Cells perform these transitions at defined cell sizes, and if born large or small adjust their growth to compensate. The cell cycle is driven by cyclin-CDK activity, and multiple signals are integrated by a single inhibitory phosphorylation site on the CDK1 enzyme. This phosphorylation is regulated by Wee1 kinase and Cdc25 phosphatase. I sought to quantify how and if cell size directly regulates CDK activity in single cells, and to what extent cyclin levels may inform cell size at division. I show that by altering the activity of Wee1 and Cdc25, the cell establishes a certain threshold cyclin-CDK for G2/M entry. Cyclin levels scale with cell size, and the probability of a cell having suprathreshold levels of cyclin dictates its probability of entering mitosis. Cell-cell variability in cyclin levels are rate limiting for cell size fidelity. The G1/S transition is similarly probabilistically controlled by cell size. Using a new single cell fluorescent biosensor of CDK activity, I show that the dose response of cyclin-CDK1 levels on CDK activity is ultrasensitive. The larger a cell, the more switch-like the dose response. This size dependent ultrasensitivity is dependent on CDK tyrosine phosphorylation. Intriguingly, in the absence of all canonical CDK control pathways, small cell size decreases intrinsic cyclin-CDK1 enzyme activity. Upon entry to mitosis, progressive substrate phosphorylation appears to be coordinated by substrate specific integration of CDK activity, rather than defined activity thresholds. This integrated-activity model of mitotic progression generates robustness to CDK inhibition. Finally, I applied the new computational and molecular tools developed throughout this thesis to demonstrate the functional ramifications of cancer associated APC/C mutations. APC/C mutations likely decrease the lethality of chromosomal instability in cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.756343  DOI: Not available
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