Aurora B prevents premature removal of spindle assembly checkpoint proteins from the kinetochore: A key role for Aurora B in mitosis
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Mark D. Gurden1, Simon J. Anderhub2,4, Amir Faisal2,3, Spiros Linardopoulos1,2
1Breast Cancer Now, Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom
2Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom
3Present address: Lahore University of Management Sciences, D.H.A. Lahore Cantt., Lahore, Pakistan
4Present address: Phenex Pharmaceuticals, Ludwigshafen am Rhein, Germany
Spiros Linardopoulos, email: Spiros.Linardopoulos@icr.ac.uk
Keywords: Aurora B, MPS1, mitosis, inhibition, SAC
Received: January 11, 2016 Accepted: June 01, 2016 Published: July 18, 2016
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.
Mark D. Gurden
Simon J. Anderhub
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