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Combinatorial Control of the Cell Cycle

  • Author(s): Holt, Liam Joseph
  • Advisor(s): Morgan, David O
  • et al.
Abstract

Cellular information is stored within chromosomes, which must be replicated and divided indefinitely. Therefore, there is tremendous pressure to create control systems that can propagate this information with minimal error. Desirable properties of regulatory networks include: non-linearity to give rise to bi-stable or switch-like transitions; the ability to integrate multiple information sources and therefore coordinate diverse cellular processes; and the ability to adapt to new pressures or opportunities to optimize the cell division process.

This thesis studies the interplay between kinases, phosphatases and ubiquitin ligases in the control of the mitotic and meiotic chromosome divisions. In mitosis, the interface between the Cdk1 kinase, Cdc14 phosphatase and the Anaphase Promoting Complex gives rise to a positive feedback loop that makes anaphase onset switch-like, thereby ensuring synchronous and faithful propagation of the 16 chromosomes of budding yeast. In meiosis, an additional kinase, Ime2, is expressed that acts as an auxiliary to Cdk1 but interacts very differently with protein phosphatases. This overlapping but distinct regulation helps enable the two sequential chromosome segregation events of sexual differentiation. Cdk1 and Ime2 are distant paralogues and co-regulate many substrates at distinct sites, the precise positions of which drift throughout evolution. The lack of pressure to conserve precise position suggests that phosphoregulation often infers regulation by simple, context-independent mechanisms that could arise frequently by chance mutation. Frequent turnover of regulatory sites should allow rapid adaptation of regulatory networks, facilitating the integration of new signaling circuits and the regulation of new biological processes.

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