Systems Biology of Mitosis

Ibrahim, Bashar GND

In mitosis, `surveillance control mechanisms' regulate transitions across the several stages of cell division. The so called `Mitotic-Spindle-Assembly-Checkpoint (MSAC)' and `Exit-From-Mitosis (EFM)' are examples of such mechanisms. MSAC ensures the correct segregation of chromosomes by preventing cell-cycle progression until all chromosomes have made proper bipolar attachments to the mitotic spindle through their kinetochores. EFM ensures that each of the two daughter nuclei receives one copy of each chromosome. Both mechanisms are seemingly regulated by the so called `Anaphase-Promoting-Complex (APC)', bound, in turn, to either `Cdc20' or `Cdh1', which are associated regulatory proteins. APC remains inactive during metaphase. In the transition from metaphase to anaphase, and only after all chromosomes are attached, a newly formed `APC:Cdc20' complex mediates the ubiquitination and degradation of the protein `Securin'; this leads, in turn, to the activation of the protein `Separase', the dissolution of the so called `Cohesin Complex', and, eventually, to chromatid separation. `APC:Cdc20' also mediates the initial phase of `Cyclin B' proteolysis. In the transition from anaphase to telophase, APC:Cdh1 completely ubiquitinates `Cyclin B', thus inactivating a protein called `CyclinB:Cdk1-Mitotic-Kinase' and triggering the exit from mitosis. Both MSAC and EFM prevent chromosome miss-segregation and aneuploidy, and their failure eventually leads to cell death; both mechanisms have been implicated in cancer.


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