Mathematical modeling and computer simulation of mitotic transition control mechanisms
The eukaryotic cell cycle is a tightly regulated sequence of processes leading from cell growth over DNA replication to the physical division of the mother into two daughter cells, each containing a complete set of chromosomes and organelles. Transition from one process to the next is guided by a number of crucial surveillance mechanisms, the so called cell cycle checkpoints. Dis-regulation of the cell cycle through checkpoint malfunction can lead to developmental defects and contribute to the development or progression of tumors. The cell cycle checkpoints are complex biochemical signal transduction networks, and their elaborate spatiotemporal dynamics are challenging to understand intuitively. Mathematical modeling and computer simulation can help to decrypt the underlying principles. This thesis approaches two important mitotic checkpoints with mathematical modeling and simulation. The highly conserved spindle assembly checkpoint (SAC) guards the transition from meta- to anaphase, preventing premature chromosome segregation to the spindle poles. In contrast to SAC, the spindle position checkpoint (SPOC) ensures that during asymmetric cell division in budding yeast mitotic exit does not occur until the spindle is properly aligned with the cell polarity axis. Although there are no known homologs, there is indication that functionally similar checkpoints exist also in animal cells. First, a detailed analysis of the kinetic consequences of localization of SAC key components to the kinetochores is presented. Second, a truly minimal, though physically meaningful kinetic model of the small Ras-linke GTPase Tem1 is established to develop the first detailed model of the SPOC. Both analyses provide valuable insights into mitotic transition control on a systems level and demonstrate that mathematical modeling, despite all unavoidable abstraction, constitutes a powerful tool for investigation of the dynamic properties of complex biological systems.
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