A small-molecule inhibitor of Haspin alters the kinetochore functions of Aurora B
Author(s)
Santaguida, Stefano; De Antoni, Anna; Maffini, Stefano; Knapp, Stefan; Musacchio, Andrea
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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.
Date issued
2012-10Department
Koch Institute for Integrative Cancer Research at MITJournal
Journal of Cell Biology
Publisher
Rockefeller University Press
Citation
De Antoni, A. et al. “A Small-molecule Inhibitor of Haspin Alters the Kinetochore Functions of Aurora B.” The Journal of Cell Biology 199.2 (2012): 269–284.
Version: Final published version
ISSN
0021-9525
1540-8140