Haspin: a newly discovered regulator of mitotic chromosome behavior

Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA.
Chromosoma (Impact Factor: 3.26). 12/2009; 119(2):137-47. DOI: 10.1007/s00412-009-0250-4

ABSTRACT The haspins are divergent members of the eukaryotic protein kinase family that are conserved in many eukaryotic lineages including animals, fungi, and plants. Recently-solved crystal structures confirm that the kinase domain of human haspin has unusual structural features that stabilize a catalytically active conformation and create a distinctive substrate binding site. Haspin localizes predominantly to chromosomes and phosphorylates histone H3 at threonine-3 during mitosis, particularly at inner centromeres. This suggests that haspin directly regulates chromosome behavior by modifying histones, although it is likely that additional substrates will be identified in the future. Depletion of haspin by RNA interference in human cell lines causes premature loss of centromeric cohesin from chromosomes in mitosis and failure of metaphase chromosome alignment, leading to activation of the spindle assembly checkpoint and mitotic arrest. Haspin overexpression stabilizes chromosome arm cohesion. Haspin, therefore, appears to be required for protection of cohesion at mitotic centromeres. Saccharomyces cerevisiae homologues of haspin, Alk1 and Alk2, are also implicated in regulation of mitosis. In mammals, haspin is expressed at high levels in the testis, particularly in round spermatids, so it seems likely that haspin has an additional role in post-meiotic spermatogenesis. Haspin is currently the subject of a number of drug discovery efforts, and the future use of haspin inhibitors should provide new insight into the cellular functions of these kinases and help determine the utility of, for example, targeting haspin for cancer therapy.

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    ABSTRACT: The current study characterizes the mitosis-associated histone dual modification on the core of histone H3: trimethylation of histone H3 lysine 79 and simultaneous phosphorylation of H3 threonine 80 (H3K79me3T80ph). Through the use of protein and microscopy-based techniques, we find that H3K79me3T80ph shares a similar spatial and temporal regulation as H3S10ph but additionally requires methyltransferase activity. In addition, we find that Aurora kinase activity is necessary for the catalysis of H3K79me3T80ph in vivo. Finally, our analysis of H3K79me3T80ph using a tissue microarray indicates that H3K79me3T80ph marks a subset of primary cutaneous melanomas with metastatic potential indicating that H3K79me3T80ph may identify a subset of invasive melanomas with a more aggressive clinical behaviour.
    11/2012; 2012:823534. DOI:10.1155/2012/823534
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    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.
    The Journal of Cell Biology 10/2012; 199(2):269-84. DOI:10.1083/jcb.201205119 · 9.69 Impact Factor
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    ABSTRACT: Post-translational histone modifications regulate many aspects of chromosome activity. Threonine 3 of histone H3 is highly conserved, but the significance of its phosphorylation is unclear, and the identity of the corresponding kinase in plants is unknown. Therefore, we characterized the candidate kinase in Arabidopsis thaliana, called AtHaspin. Recombinant AtHaspin in vitro phosphorylates histone H3 at threonine 3. Reduction of H3 threonine 3 phosphorylation level and reduced chromatin condensation in interphase nuclei by AtHaspin RNAi supports the proposition that this kinase is involved in histone H3 phosphorylation in vivo in mitotic cells. In addition, we provide a developmental function for a Haspin kinase. At the whole plant level, altered expression of the kinase induced pleiotropic phenotypes with defects in floral organs and vascular tissue. It reduced fertility and modified adventitious shoot apical meristems that then gave rise to plants with multi-rosettes and multi-shoots. Haspin mutant embryos frequently showed alteration in division plane orientation that could be traced back to the earliest divisions of embryo development, thus Haspin contributes to embryonic patterning.
    The Plant Journal 07/2011; 68(3):443-54. DOI:10.1111/j.1365-313X.2011.04699.x · 6.82 Impact Factor


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