Sensing centromere tension: Aurora B and the regulation of kinetochore function

doi:10.1016/j.tcb.2010.10.007

Trends in Cell Biology

Volume 21, Issue 3, March 2011, Pages 133-140

https://doi.org/10.1016/j.tcb.2010.10.007 Get rights and content

Maintaining genome integrity during cell division requires regulated interactions between chromosomes and spindle microtubules. To ensure that daughter cells inherit the correct chromosomes, the sister kinetochores must attach to opposite spindle poles. Tension across the centromere stabilizes correct attachments, whereas phosphorylation of kinetochore substrates by the conserved Ipl1/Aurora B kinase selectively eliminates incorrect attachments. Here, we review our current understanding of how mechanical forces acting on the kinetochore are linked to biochemical changes to control chromosome segregation. We discuss models for tension sensing and regulation of kinetochore function downstream of Aurora B, and mechanisms that specify Aurora B localization to the inner centromere and determine its interactions with substrates at distinct locations.

Introduction

The accurate segregation of chromosomes during cell division is essential to maintain genomic stability. In eukaryotic cells, the microtubule-based mitotic spindle generates forces to align the sister chromatids at the metaphase plate, and then to pull the sister chromatids in opposite directions to segregate them to the two daughter cells. The kinetochore assembles at the centromere of each chromosome to mediate interactions with spindle microtubules. Kinetochores can initially bind to microtubules in any configuration, but accurate chromosome segregation requires that each pair of sister kinetochores ultimately attach to microtubules from opposite spindle poles (bi-orientation). Although there is a bias towards bi-orientation owing to geometric constraints imposed by chromosome structure 1, 2, frequent errors in kinetochore–microtubule attachments do occur 3, 4 and would lead to unequal segregation if uncorrected. Therefore, kinetochore–microtubule attachments must be carefully regulated: incorrect attachments are destabilized and correct attachments are stabilized. In this way, all kinetochores eventually reach the correct attachment state in a trial-and-error process, with destabilization providing a fresh opportunity to bi-orient (reviewed in [5]). Defining the mechanism that selectively stabilizes only correct attachments is crucial to understanding proper chromosome segregation. Here, we review recent work in an attempt to understand the molecular mechanisms by which erroneous attachments are detected and corrected, focusing on the role of Aurora B kinase in this process. We discuss the processes that act upstream to control the activity of Aurora B and its phosphorylation of kinetochore substrates, and the downstream consequences of Aurora B phosphorylation for kinetochore activity and function.

Section snippets

Regulating attachments: reconciling mechanical and molecular mechanisms

Classic experiments by Bruce Nicklas using micromanipulation in insect spermatocyes provided direct experimental evidence that attachments are stabilized through tension across the centromere. In cells, this tension is established as spindle microtubules pull bi-oriented kinetochores in opposite directions. Experimentally induced tension, applied with a glass microneedle, stabilizes unipolar attachments that are otherwise unstable 6, 7. These experiments laid the foundation for a model to

How is tension sensed?

A key question for understanding the error correction process is how correct and incorrect attachments are distinguished. Based on the tension hypothesis established by the Nicklas micromanipulation experiments, phosphorylation of Aurora B substrates should respond to tension. A priori, there are multiple ways in which this regulation could be accomplished. Mechanical stretching can lead to various functional responses; for example, by exposing binding sites or phosphorylation sites,

Connecting Aurora B activity to changes in kinetochore function

As described above, the position of Aurora B relative to its substrates (Table 1) is a key factor in controlling the phosphorylation of its downstream targets. As defined substrates for Aurora B have distinct localizations within the kinetochore, this position has important implications for their relative phosphorylation. Those substrates that are located proximally to Aurora B are likely to be constitutively phosphorylated at the times when Aurora B localizes to centromeres (prophase until

How does Aurora B touch its substrates?

The spatial separation model explains how chromosome bi-orientation can be sensed through changes in tension across the centromere, which is a crucial component for any model of error correction. As discussed above, this model is based on the idea that local Aurora B activity at the outer kinetochore depends on the distance from the inner centromere, where the kinase is localized. Because these localizations are clearly distinct from each other, possibly separated by as much as 100 nm, it is

Concluding remarks

In conclusion, recent work has provided important insights that explain how mechanical forces at kinetochores are translated into chemical signals to ensure correct kinetochore–microtubule attachments, as envisioned by Nicklas more than 40 years ago. This review has focused on Aurora B in the context of inter-kinetochore tension, or stretching of the centromere in response to sister kinetochore bi-orientation. However, recent evidence indicates that stretching within a single kinetochore, which

Acknowledgments

Research in our laboratories is supported by grants from the US National Institutes of Health (GM083988 to M.A. Lampson and GM088313 to I.M. Cheeseman) and the Searle Scholars Program. We thank the (mostly) anonymous reviewers for their helpful, thoughtful and constructive comments on the manuscript.

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For correct chromosome segregation in mitosis, sister kinetochores must interact with microtubules from opposite spindle poles (biorientation). For this, aberrant kinetochore-microtubule interaction must be resolved (error correction) by Aurora B kinase. Once biorientation is formed, tension is applied on kinetochore-microtubule interaction, stabilizing this interaction. The mechanism for this tension-dependent process has been debated. Here, we study how Aurora B localizations at different kinetochore sites affect the biorientation establishment and maintenance in budding yeast. Without the physiological Aurora B-INCENP recruitment mechanisms, engineered recruitment of Aurora B-INCENP to the inner kinetochore, but not to the outer kinetochore, prior to biorientation supports the subsequent biorientation establishment. Moreover, when the physiological Aurora B-INCENP recruitment mechanisms are present, an engineered Aurora B-INCENP recruitment to the outer kinetochore, but not to the inner kinetochore, during metaphase (after biorientation establishment) disrupts biorientation, which is dependent on the Aurora B kinase activity. These results suggest that the spatial separation of Aurora B from its outer kinetochore substrates is required to stabilize kinetochore-microtubule interaction when biorientation is formed and tension is applied on this interaction. Meanwhile, Aurora B exhibits dynamic turnover on the centromere/kinetochore during early mitosis, a process thought to be crucial for error correction and biorientation. However, using the engineered Aurora B-INCENP recruitment to the inner kinetochore, we demonstrate that, even without such a turnover, Aurora B-INCENP can efficiently support biorientation. Our study provides important insights into how Aurora B promotes error correction for biorientation in a tension-dependent manner.
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Trends in Cell Biology

ReviewSensing centromere tension: Aurora B and the regulation of kinetochore function

Introduction

Section snippets

Regulating attachments: reconciling mechanical and molecular mechanisms

How is tension sensed?

Connecting Aurora B activity to changes in kinetochore function

How does Aurora B touch its substrates?

Concluding remarks

Acknowledgments

Curr. Biol.

Cell

Cell

Curr. Biol.

J. Biol. Chem.

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Exp. Cell Res.

Cell

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Curr. Biol.

Cell

Curr. Biol.

Dev. Cell

Mol. Cell

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Curr. Biol.

Cell

Cell

Cell

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Curr. Biol.

Cell

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Curr. Biol.

Dev. Cell

Dev. Cell

Curr. Opin. Cell Biol.

Chem. Biol.

Curr. Biol.

Dev. Cell

Curr. Biol.

Cell

Mol. Cell

J. Biol. Chem.

Dev. Cell

Cell

Dev. Cell

The centromere geometry essential for keeping mitosis error free is controlled by spindle forces

Nature

Chromosome mal-orientation and reorientation during mitosis

Cell Motil. Cytoskeleton

Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells

J. Cell Biol.

How cells get the right chromosomes

Science

Chromosome micromanipulation. 3. Spindle fiber tension and the reorientation of mal-oriented chromosomes

J. Cell Biol.

Elements of error correction in mitosis: microtubule capture, release, and tension

J. Cell Biol.

Isolation and characterization of chromosome-gain and increase-in-ploidy mutants in yeast

Genetics

The conserved protein kinase Ipl1 regulates microtubule binding to kinetochores in budding yeast

Genes Dev.

Type 1 protein phosphatase acts in opposition to IpL1 protein kinase in regulating yeast chromosome segregation

Mol. Cell Biol.

Aurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases

J. Cell Sci.

Chromosomal passengers: conducting cell division

Nat. Rev. Mol. Cell Biol.

The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint

J. Cell Biol.

Review
Sensing centromere tension: Aurora B and the regulation of kinetochore function