ABSTRACT
During the prometaphase stage of mitosis, the cell builds a bipolar spindle of microtubules that mechanically segregates sister chromatids between two daughter cells in anaphase. The spindle assembly checkpoint (SAC) is a quality control mechanism that monitors proper attachment of microtubules to chromosome kinetochores during prometaphase. Segregation occurs only when each chromosome is bi-oriented with each kinetochore pair attached to microtubules emanating from opposite spindle poles. Overexpression of the protein kinase Aurora A is a feature of various cancers and is thought to enable tumour cells to bypass the SAC, leading to aneuploidy. Here, we took advantage of a chemical and chemical-genetic approach to specifically inhibit Aurora A kinase activity in late prometaphase. We observed that a loss of Aurora A activity directly affects SAC function, that Aurora A is essential for maintaining the checkpoint protein Mad2 on unattached kinetochores and that inhibition of Aurora A leads to loss of the SAC, even in the presence of nocodazole or Taxol. This is a new finding that should affect the way Aurora A inhibitors are used in cancer treatments.
This article has an associated First Person interview with the first authors of the paper.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: T.C., A.D., C.P.; Methodology: T.C., A.D., A.P.D., D.R., E.W., C.P.; Investigation: T.C., A.D., A.P.D., E.W., C.P.; Writing - original draft: T.C., C.P.; Writing - review & editing: T.C., E.W., C.P.; Supervision: E.W., C.P.; Project administration: C.P.; Funding acquisition: C.P.
Funding
This work was supported by the Centre National de la Recherche Scientifique, Université de Rennes 1, Institut National du Cancer, Ligue Contre le Cancer (Equipe Labelisée 2014), and Agence Nationale de la Recherche (Aurora).
Supplementary information
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.191353.supplemental
- Received April 25, 2016.
- Accepted March 12, 2018.
- © 2018. Published by The Company of Biologists Ltd
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