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Mathematical models of mitosis

Mitosis is a critical stage in the cell cycle process that is required for growth and replacement of worn out cells. Elucidating underlying mechanisms could be the key to understanding various diseases and developing innovative therapies.

Health

EU-funded researchers from eight different European countries collaborated under the project MITOSYS (Systems biology of mitosis) to develop mathematical models of mitotic cell division in humans at a systems level. Researchers focused on four key aspects of mitosis — spindle assembly, spindle assembly checkpoint and kinetochores, segregation of mitotic chromosomes and mitotic exit. MITOSYS generated kinetic and quantitative data on mitotic proteins using microscopic imaging, biochemistry, biophysics, single-molecule techniques and proteomics. Kinetochores, kinetochore sub-complexes and checkpoint signalling were reconstituted and the researchers produced mathematical models describing various aspects of chromosome segregation. At the end of the process, a mathematical model for mitotic exit was implemented. Researchers experimentally verified the mathematical models for the error-correction mechanism of chromosome bi-orientation and the spindle assembly checkpoint. They also quantitatively described spatial control of the biochemical regulatory network and temporal ordering of mitotic events (anaphase and cytokinesis). These results were also confirmed by experiments. Integrating these, a comprehensive model of all phases of mitosis has been established that combines these steps with regulation by several key cell cycle regulators. Efforts are ongoing to further refine and validate these models even beyond the end of the project. MITOSYS successfully developed new technologies to facilitate the generation of kinetic and quantitative data on protein function in human cells. For instance, they established a quantitative microscopy imaging system with automated data acquisition and analysis that enabled the visualisation of key mitotic proteins. Project members organised a training course on mathematical modelling in October 2014. Public exhibitions on systems biology of mitosis and its relevance to health and disease – "Lens on Life" were displayed in three European cities (Rome, London and Heidelberg) along with the documentary film "Meetings of Minds". An integral part of the exhibitions is an innovative documentary film on art and science around mitosis that can now be viewed via the project website. MITOSYS project activities have contributed to the development of a systems level description of mitosis — a feat not achieved to date. As correct execution of mitosis is essential for health, potential applications include understanding diseases and drug development.

Keywords

Mathematical model, mitosis, spindle assembly, kinetochore, drug development

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