Aurora B prevents premature removal of spindle assembly checkpoint proteins from the kinetochore: A key role for Aurora B in mitosis

// Mark D. Gurden 1 , Simon J. Anderhub 2, 4 , Amir Faisal 2, 3 and Spiros Linardopoulos 1, 2 1 Breast Cancer Now, Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom 2 Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom 3 Present address: Lahore University of Management Sciences, D.H.A. Lahore Cantt, Lahore, Pakistan 4 Present address: Phenex Pharmaceuticals, Ludwigshafen am Rhein, Germany Correspondence to: Spiros Linardopoulos, email: Spiros.Linardopoulos@icr.ac.uk Keywords: Aurora B; MPS1; mitosis; inhibition; SAC Received: January 11, 2016 Accepted: June 01, 2016 Epub: July 18, 2016 Published: April 13, 2018 ABSTRACT Accurate chromosome segregation is dependent on the spindle assembly checkpoint (SAC). In current models, the key direct role of Aurora B in the SAC has been suggested to be to promote rapid kinetochore localisation of MPS1, allowing MPS1 to generate the checkpoint signal. However, Aurora B is also thought to play an indirect role in the SAC through the destabilisation of kinetochore-microtubule (KT-MT) attachments. Here, we demonstrate that Aurora B activity is not required for the kinetochore recruitment of the majority of SAC proteins. More importantly, we show that the primary role of Aurora B in the SAC is to prevent the premature removal of SAC proteins from the kinetochore, which is strictly dependent on KT-MT interactions. Moreover, in the presence of KT-MT interactions, Aurora B inhibition silences a persistent SAC induced by tethering MPS1 to the kinetochore. This explains the highly synergistic interaction between Aurora B and MPS1 inhibitors to override the SAC, which is lost when cells are pre-arrested in nocodazole. Furthermore, we show that Aurora B and MPS1 inhibitors synergistically kill a panel of breast and colon cancer cell lines, including cells that are otherwise insensitive to Aurora B inhibitors alone. These data demonstrate that the major role of Aurora B in SAC is to prevent the removal of SAC proteins from tensionless kinetochores, thus inhibiting premature SAC silencing, and highlights a therapeutic strategy through combination of Aurora B and MPS1 inhibitors.