Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.728941
Title: Systems-level analysis of the mitotic checkpoint
Author: Hutter, Lukas Hermann
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Abstract:
The mitotic checkpoint regulates a critical transition in the eukaryotic cell cycle. It delays exit from mitosis until all chromosomes have become bi-oriented. In spite of an impressive body of work uncovering mechanistic aspects of the mitotic checkpoint, a detailed understanding of how the mitotic checkpoint operates as a control system continues to evade us. Here, I present three systems-biological studies aimed at elucidating distinct aspects of the mitotic checkpoint control system. Using a combination of dedicated experiments and mathematical modelling, we investigate the fragile response of the mitotic checkpoint to precocious separation of sister chromatids in Drosophila neuroblasts. We show that the lack of a robust response to precocious loss of sister chromatid cohesion results from systems-level crosstalk between error correction and the checkpoint effector module. Applying dynamical systems theory in the analysis of a live-cell imaging dataset following the degradation of APC/C:Cdc20-susbtrates in RPE1 and HeLa cells that are arrested in prometaphase and treated with different doses of CDK1 inhibitor, we present a simple mathematical model of the mitotic checkpoint as parsimonious explanation for the observed response to CDK1 inhibition. The model gives rise to a bistable switch, which is discussed as a useful tool to conceptualise the transition of from prometaphase to metaphase and from metaphase to anaphase in terms of disengagement and inactivation of the mitotic checkpoint. Employing a simple mathematical model of phosphatase regulation at mitotic exit as a tool in the analysis of a phosphoproteomics dataset, we examine how the decision to silence the checkpoint is dispatched to initiate diverse processes underpinning mitotic exit. We identify new substrates of the phosphatase PP2A:B55, and describe a mechanism whereby substrates are recognised by PP2A:B55 and their rate of dephosphorylation is encoded electrostatically.
Supervisor: Novak, Bela Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.728941  DOI: Not available
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