Mathematical modelling of mitotic exit control in budding yeast cell cycle

Thesis

The operating principles of complex regulatory networks are more easily understood with mathematical modelling than by intuitive reasoning. In this thesis, I study the dynamics of the mitotic exit control system in budding yeast. I present a comprehensive mathematical model, which provides a system’s-level understanding of the mitotic exit process. This model captures the dynamics of classic experimental situations reported in the literature, and overcomes a number of limitations present in previous models.

Analysis of the model led to a number of breakthroughs in the understanding of mitotic exit control. Firstly, numerical analysis of the model quantified the dependence of mitotic exit on the proteolytic and non-proteolytic functions of separase. It was shown that the requirement for the non-proteolytic function of separase depends on cyclin-dependent kinase activity. Secondly, APC/Cdc20 is a critical node that controls the phosphatase (Cdc14) branch and both cyclin (Clb2 and Clb5) branches of the cell cycle regulatory network. Thirdly, the model proved to be a useful tool for the systematic analysis of the recently discovered phenomenon of Cdc14 endocycles.

Most proteins belonging to the cell cycle control network are regulated at the level of synthesis, degradation and activity. Presumably, these multiple layers of regulation facilitate robust cell cycle behaviour in the face of genetic and environmental perturbations. To falsify this hypothesis, I subjected the model to global parameter perturbations and tested viability against pre-defined criteria. According to these analyses, the regulated transcription and degradation of proteins make different contributions to cell cycle control. Regulated degradation confers cell cycle oscillations with robustness against perturbations, while regulated transcription plays a major role in controlling the period of these oscillations. Both regulated transcription and degradation are part of important feedback loops, that combined promote robust behaviour in the face of parametric variations.

Authors: Freire, P; Paula Freire

• Publication date: 2012
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: mathematical model; cell cycle; mitotic exit; budding yeast
• Subjects: Biochemistry