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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.

Original publication

DOI

10.1083/jcb.201205119

Type

Journal article

Journal

J Cell Biol

Publication Date

15/10/2012

Volume

199

Pages

269 - 284

Keywords

Aurora Kinase B, Aurora Kinases, Autoantigens, Cell Cycle Proteins, Cell Line, Tumor, Centromere Protein A, Chromosomal Proteins, Non-Histone, Chromosome Segregation, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Kinetochores, M Phase Cell Cycle Checkpoints, Nocodazole, Nuclear Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Signal Transduction, Tubercidin