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.
Highlights
The correct functioning of the spindle assembly checkpoint (SAC) is essential for maintaining genomic stability
MPS1 and Aurora B inhibitors strongly synergise in overriding the SAC, through simultaneously inhibiting SAC establishment caused by MPS1 inhibition and maintenance caused by Aurora B inhibition, inducing rapid cell death in cancer cell lines
Once the checkpoint is established in nocodazole, our data shows that Aurora B activity is largely dispensable for SAC production, since, despite reduced MPS1 and BUBR1 kinetochore localisation, all other SAC proteins continue to be robustly recruited and the mitotic checkpoint complex (MCC) formed
Summary
The correct functioning of the spindle assembly checkpoint (SAC) is essential for maintaining genomic stability. Central to SAC signalling is the recruitment of a network of proteins to unattached kinetochores, resulting in the formation of the mitotic checkpoint complex (MCC; CDC20/BUBR1/BUB3/ MAD2), which inhibits the Anaphase Promoting Complex/ Cyclosome (APC/C) and progression into anaphase [1]. Phosphorylation is a major mechanism for regulating protein activity and localisation during mitosis, two seminal kinases being Aurora B and MPS1. Aurora B forms part of the Chromosome Passenger Complex (CPC), which localises to the centromere during mitosis where it corrects erroneous chromosomemicrotubule attachment errors, as well as regulating the SAC [2]. MPS1 localises to the outer kinetochore in early mitosis and is required for the recruitment of SAC proteins to the kinetochore throughout mitosis, as well as catalysing the formation of the MCC [3,4,5,6]. MPS1 plays a role in chromosome alignment by www.oncotarget.com competing with microtubules for binding NDC80 complex [1, 7, 8]
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