The final stage of the cell division cycle (mitosis) involves the compaction of the duplicated genome into chromatid pairs (chromosomes), which are then aligned in the centre of the cell. For cells to exit mitosis they must separate each chromatid to opposite sides of the cell and then divide to create two identical daughter cells. Failure to exit from mitosis correctly results in unequal division of genetic material, and is the origin of chromosomal instability (CIN). High-resolution mapping of structural variants in the cancer genome shows that solid tumours with CIN are associated with poorer outcomes, rapidly acquire multi-drug resistance, and are refractory to most chemotherapeutics. Therefore, to comprehend how cancer cells become chromosomally unstable, it is critical to understand the mechanisms controlling mitotic exit.
Recently, we demonstrated that correct mitotic progression was dependent on maintaining a tightly regulated balance between the activities of the phosphatase PP2A, and kinase CDK1 [1]. Furthermore, we identified the novel mitotic kinase Greatwall as the master regulator of this balance, a finding that has dramatically altered the understanding of cell division [2]. This axis is deregulated in over 69% of Invasive Breast Carcinomas and 25% of all breast cancers (TCGA, Provisional). Partial inhibition of Cdk1 activity during G2 phase results in a highly aberrant mitosis, with cells attempting to perform cytokinesis and metaphase simultaneously, resulting in the random partitioning of whole chromosomes. Ultimately, this produces a significant increase in the proportion of viable multi-nuclear polyploid cells. Treatment with low doses of okadaic acid, which primarily inhibits PP2A, rescues the mitotic defects and increases the number of cells that completed a normal mitosis. Taken together these results show that the Gwl-Cdk1-PP2A axis is the ultimate controller of mitotic exit and chromosome instability.