Chromosome 'by-Aurora-ientation' during mitosis

New evidence from three separate laboratories, published recently in Science, has shown that centromere positioning of the CPC (chromosomal passenger complex) during early mitosis is achieved through direct interaction between the CPP (chromosomal passenger protein) survivin and histone H3. In essence, an acidic pocket in the BIR (baculovirus inhibitor of apoptosis repeat) domain of survivin binds to the NH2 tail of histone H3 specifically when it is phosphorylated at threonine 3, a mark that is placed by the mitotic kinase, haspin. These data are significant, as they describe a fundamental mechanism, conserved throughout eukaryotes, which is essential for chromosome biorientation and the maintenance of genome stability during mitosis.     

AtHaspin phosphorylates histone H3 at threonine 3 during mitosis and contributes to embryonic patterning in Arabidopsis

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.     

Polo‐like kinase‐1 triggers histone phosphorylation by Haspin in mitosis

Histone modifications coordinate the chromatin localization of key regulatory factors in mitosis. For example, mitotic phosphorylation of Histone H3 threonine‐3 (H3T3ph) by Haspin creates a binding site for the chromosomal passenger complex (CPC). However, how these histone modifications are spatiotemporally controlled during the cell cycle is unclear. Here we show that Plk1 binds to Haspin in a Cdk1‐phosphorylation‐dependent manner. Reducing Plk1 activity decreases the phosphorylation of Haspin and inhibits H3T3ph, particularly in prophase, suggesting that Plk1 is required for initial activation of Haspin in early mitosis. These studies demonstrate that Plk1 can positively regulate CPC recruitment in mitosis.     

Haspin inhibition delays cell cycle progression through interphase in cancer cells

Haspin (Haploid Germ Cell-Specific Nuclear Protein Kinase) is a serine/threonine kinase pertinent to normal mitosis progression and mitotic phosphorylation of histone H3 at threonine 3 in mammalian cells. Different classes of small molecule inhibitors of haspin have been developed and utilized to investigate its mitotic functions. We report herein that applying haspin inhibitor CHR-6494 or 5-ITu at the G1/S boundary could delay mitotic entry in synchronized HeLa and U2OS cells, respectively, following an extended G2 or the S phase. Moreover, late application of haspin inhibitors at S/G2 boundary is sufficient to delay mitotic onset in both cell lines, thereby, indicating a direct effect of haspin on G2/M transition. A prolonged interphase duration is also observed with knockdown of haspin expression in synchronized and asynchronous cells. These results suggest that haspin can regulate cell cycle progression at multiple stages at both interphase and mitosis.