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Updated: Mar 8, 2026
Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations
Published on: September 20, 2019
Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in
Fazhi Yu1, Ya Jiang1, Lucy Lu2
1Key Laboratory of Innate Immunity and Chronic Disease of CAS, Innovation Center for Cell Biology, School of Life Sciences, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China , Hefei, China.
Abstract:
Aurora-A kinase functions mainly in centrosome maturation, separation and spindle formation. It has also been found to be amplified or overexpressed in a range of solid tumors, which is linked with tumor progression and poor prognosis. Importantly, Aurora-A inhibitors are being studied in a number of ongoing clinical trials. However, whether and how Aurora-A has a role in the regulation of the mitotic checkpoint is controversial. Additionally, the function of nuclear-accumulated Aurora-A in late G2 phase is not clear. Here we show that knockout, inhibition or blockade of the nuclear entry of Aurora-A severely decreased the centromere localization of Aurora-B and the phosphorylation of histone H3 threonine 3 (H3T3-ph) mediated by the kinase Haspin in late G2 phase. We further reveal that nuclear-accumulated Aurora-A phosphorylates Haspin at multiple sites at its N-terminus and that this promotes H3T3-ph and the rapid recruitment to the centromere of the chromosomal passenger complex. In addition, Aurora-A facilitates the association of Aurora-B with their common substrates: Haspin and Plk1. Notably, these functions of Aurora-A are mostly independent of Plk1. Thus we demonstrate that, in late G2 and prophase, Aurora-A phosphorylates Haspin to trigger the Haspin-H3T3-ph-Aurora-B positive feedback loop that supports the timely establishment of the chromosomal passenger complex and the mitotic checkpoint before spindle assembly.
Insights
Aurora-A kinase regulates key mitotic events by phosphorylating Haspin, initiating a feedback loop essential for the chromosomal passenger complex and mitotic checkpoint establishment before spindle assembly.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Aurora-A kinase is crucial for centrosome function and spindle formation.
- Its overexpression in solid tumors correlates with poor prognosis, and inhibitors are in clinical trials.
- The role of Aurora-A in mitotic checkpoint regulation and its nuclear function in G2 phase remain unclear.
Purpose of the Study:
- To elucidate the role of nuclear-accumulated Aurora-A in regulating the mitotic checkpoint.
- To investigate the mechanism by which Aurora-A influences centromere localization of Aurora-B and histone modification.
- To determine the relationship between Aurora-A, Haspin, and Aurora-B in early mitosis.
Main Methods:
- Gene knockout and inhibition of Aurora-A.
- Blocking nuclear entry of Aurora-A.
- Assessing centromere localization of Aurora-B and histone H3 threonine 3 phosphorylation (H3T3-ph).
- Phosphorylation site analysis of Haspin by Aurora-A.
Main Results:
- Aurora-A knockout, inhibition, or blockade of nuclear entry reduced centromere localization of Aurora-B and Haspin-mediated H3T3-ph.
- Nuclear Aurora-A directly phosphorylates Haspin, promoting H3T3-ph and chromosomal passenger complex recruitment.
- Aurora-A facilitates Aurora-B association with Haspin and Plk1, largely independent of Plk1.
Conclusions:
- Aurora-A phosphorylates Haspin in late G2/prophase, initiating a positive feedback loop involving Haspin-H3T3-ph-Aurora-B.
- This loop ensures timely establishment of the chromosomal passenger complex and mitotic checkpoint prior to spindle assembly.
- Nuclear Aurora-A plays a critical, previously unrecognized role in orchestrating key mitotic events through Haspin activation.
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