A small-molecule inhibitor of Haspin alters the kinetochore functions of Aurora B

Anna De Antoni, Stefano Maffini, Stefan Knapp, Andrea Musacchio, Stefano Santaguida

Research output: Contribution to journalArticlepeer-review

Abstract

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 languageEnglish
Pages (from-to)269-284
Number of pages16
JournalJournal of Cell Biology
Volume199
Issue number2
DOIs
Publication statusPublished - Oct 15 2012

ASJC Scopus subject areas

  • Cell Biology

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