In silico Investigation of Possible Mitotic Checkpoint Signalling Mechanisms
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The mitotic checkpoint is the major bio-chemical pathway acting to ensure stable genome content in cell division. A delay in chromosome segregation is enforced as long as at least one kinetochore is in lack of proper attachment to the mitotic spindle, something that prevents premature initiation of anaphase and uneven chromosome distribution. The backbone of the mitotic checkpoint control system is established as the production of a wait-anaphase signal at the unattached kinetochores. However, how this signal is able to support a functional checkpoint is unclear. To explore the performance of the wait-anaphase signal in terms of providing the mitotic checkpoint with high fidelity, a mathematical modelling framework is constructed that simulates the spatially distinct production of anaphase inhibitors, their diffusion in the cytoplasm and interference with the anaphase-promoting machinery. The model is used to analyse the performance of several different signalling mechanisms, with emphasis on testing the ability to maintain tight inhibition and allow rapid release of the anaphase promoter.