Trends in Cell Biology
ReviewSensing centromere tension: Aurora B and the regulation of kinetochore function
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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