Survivin and Aurora Kinase A control cell fate decisions during mitosis.

Abstract

The spindle assembly checkpoint (SAC) delays the metaphase-to-anaphase transition. Aurora kinase A (AURKA) inactivation has been shown to cause premature exit from mitosis in the presence of an unsatisfied SAC. We report for the first time that centromeric AURKA interacts with survivin during prometaphase. Notably, depleting or inhibiting AURKA activity at this stage causes mislocalisation of the CPC and BubR1, which compromises the SAC and can lead to mitotic slippage. Furthermore, we show that AURKA binds directly to the BIR domain of survivin at a position distinct from AURKB and indirectly to it via its C terminus. We find the interaction peaks during prometaphase but persists into late mitosis. Importantly, we demonstrate that cells with high levels of survivin are particularly vulnerable to mitotic slippage induced by the AURKA inhibitor, MLN8237/ Alisertib. Alisertib enables both normal and transformed cells with high levels of survivin to activate the APC/C prematurely, as observed by the destruction of cyclin B and securin. Thus, a high expression of survivin can alter cell fate decisions at mitosis and lead to genetic instability, a key hallmark in cancer.