Journal
JOURNAL OF CELL BIOLOGY
Volume 199, Issue 2, Pages 269-284Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201205119
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Funding
- European Union
- Italian Association for Cancer Research (AIRC)
- Human Frontier Science Program
- Italian Foundation for Cancer Research (FIRC)
- SGC
- Canadian Institutes for Health Research [1097737]
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Abbott
- Takeda
- Pfizer
- Eli Lilly
- Novartis Research Foundation
- Ontario Ministry of Research and Innovation
- Wellcome Trust
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By phosphorylating Thr3 of histone H3, Haspin promotes centromeric recruitment of the chromosome passenger complex (CPC) during mitosis. Aurora B kinase, a CPC subunit, sustains chromosome bi-orientation and the spindle assembly checkpoint (SAC). Here, we characterize the small molecule 5-iodotubercidin (5-ITu) as a potent Haspin inhibitor. In vitro, 5-ITu potently inhibited Haspin but not Aurora B. Consistently, 5-ITu counteracted the centromeric localization of the CPC without affecting the bulk of Aurora B activity in HeLa cells. Mislocalization of Aurora B correlated with dephosphorylation of CENP-A and Hec1 and SAC override at high nocodazole concentrations. 5-ITu also impaired kinetochore recruitment of Bub1 and BubR1 kinases, and this effect was reversed by concomitant inhibition of phosphatase activity. Forcing localization of Aurora B to centromeres in 5-ITu also restored Bub1 and BubR1 localization but failed to rescue the SAC override. This result suggests that a target of 5-ITu, possibly Haspin itself, may further contribute to SAC signaling downstream of Aurora B.
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