The right place at the right time: Aurora B kinase localization to centromeres and kinetochores

Abstract

The fidelity of chromosome segregation during mitosis is intimately linked to the function of kinetochores, which are large protein complexes assembled at sites of centromeric heterochromatin on mitotic chromosomes. These key "orchestrators" of mitosis physically connect chromosomes to spindle microtubules and transduce forces through these connections to congress chromosomes and silence the spindle assembly checkpoint. Kinetochore-microtubule attachments are highly regulated to ensure that incorrect attachments are not prematurely stabilized, but instead released and corrected. The kinase activity of the centromeric protein Aurora B is required for kinetochore-microtubule destabilization during mitosis, but how the kinase acts on outer kinetochore substrates to selectively destabilize immature and erroneous attachments remains debated. Here, we review recent literature that sheds light on how Aurora B kinase is recruited to both centromeres and kinetochores and discuss possible mechanisms for how kinase interactions with substrates at distinct regions of mitotic chromosomes are regulated.

Keywords: Hec1; aurora kinases; cellular reproduction; kinetochores; microtubule; spindle.

Figure 1.. Kinetochore-microtubule attachments in mitosis.

(A) In early mitosis, kinetochore-microtubule attachment errors are common, Aurora B kinase activity is high at outer kinetochores, and kinetochore-microtubule turnover is high to prevent premature stabilization of attachments. (B) In late mitosis, kinetochore-microtubule errors are infrequent, Aurora B kinase activity is low at outer kinetochores, and kinetochore-microtubule turnover is low to promote attachment stabilization. (C) Types of kinetochore-microtubule attachments are shown. Erroneous attachments include monotelic, syntelic, and merotelic attachments. Monotelic attachments occur when one kinetochore is attached to microtubules emanating from one spindle pole, and its sister kinetochore is unattached. Syntelic attachments occur when both sister kinetochores are attached to microtubules emanating from the same spindle pole. Merotelic attachments occur when one sister kinetochore is attached to microtubules emanating from one pole, and its sister is attached to microtubules emanating from both spindle poles. Correct, amphitelic attachments, in which one sister is attached to microtubules emanating from one spindle pole and its sister is attached to microtubules emanating from the opposite spindle pole, are also shown.

Figure 2.. Spatial positioning model for Aurora B kinase-mediated regulation of kinetochore-microtubule attachment stability.

In this proposed mechanism Aurora B kinase is recruited to and activated at the inner centromere, and active kinase emanates as a diffusible gradient outward towards kinetochores. In early mitosis, when kinetochores lack stable microtubule-attachments, kinetochores are physically close to the inner centromere, and the kinase gradient reaches and phosphorylates kinetochore substrates, which promotes kinetochore-microtubule turnover. As stable attachments form and kinetochores experience pulling forces from the dynamics of attached microtubule plus ends, kinetochores are stretched away from the inner centromere region and out of the reach of the active kinase. Kinetochore substrate phosphorylation decreases, and attachments to microtubules are further stabilized.

Figure 3.. Direct recruitment model for Aurora B kinase-mediated regulation of kinetochore-microtubule attachment stability.

In this proposed mechanism, Aurora B kinase is directly recruited to both centromeres and kinetochores. In early mitosis, the kinase and its CPC cofactors are recruited to the inner centromere (via the phospho-histone marks pH2A and pH3, see Figure 4) and to kinetochores through specific kinetochore receptors that likely reside in both the inner and outer kinetochore. As mitosis progresses and tension-generating kinetochore-microtubule attachments form, changes in kinetochore architecture (and in specific CPC receptor protein structure) lead to loss of the kinetochore-associated Aurora B kinase/CPC binding sites and subsequent eviction of Aurora B and the CPC from kinetochores. Kinetochore substrate phosphorylation is reduced, and kinetochore-microtubule attachments are further stabilized. In this cartoon, while the CPC accumulates at inner centromeres in early mitosis, its activity increases in this region during later mitosis (see text for details). Activity on only one kinetochore of each pair is shown for clarity.

Figure 4.. Recruitment pathways for centromere-localized Aurora B kinase.

(A) Phosphorylated histone H3 recruits the CPC to inner centromeres through direct binding of Survivin. Phosphorylated histone H2A recruits the CPC to kinetochore-proximal outer centromere regions through Sgo1-dependent binding of the CPC, likely through direct interaction between Sgo1 and Borealin. Once recruited to the outer centromere, this population of the kinase is possibly translocated to the inner centromere (indicated by inward-directed arrows). (B) In Bub1 inhibited cells, phosphorylated histone H3 recruits the CPC to inner centromeres, and this activity is sufficient to support error-free chromosome segregation. (C) In Haspin inhibited cells, phosphorylated histone H2A recruits the CPC to kinetochore-proximal outer centromere regions. In this case, the kinase remains localized to these regions and is not relocated to inner centromeres. Similar to the scenario in (B), kinase recruitment to this region is sufficient to support error-free chromosome segregation. (D) In Bub1- and Haspin-inhibited cells, Aurora B fails to localize to centromeres, and chromosome segregation is impaired. In all cases (A-D), kinetochore-associated Aurora B kinase activity (in early mitosis) remains high, regardless of centromeric accumulation of the kinase. This model is based on data from references [56, 61, 62]