Kinetochores and disease: keeping microtubule dynamics in check!

Abstract

The essential role of microtubules in cell division has long been known. Yet the mechanism by which microtubule attachment to chromosomes at kinetochores is regulated has only been recently revealed. Here, we review the role of kinetochore-microtubule (kMT) attachment dynamics in the cell cycle as well as emerging evidence linking deregulation of kMT attachments to diseases where chromosome mis-segregation and aneuploidy play a central role. Evidence indicates that the dynamic behavior of kMTs must fall within narrow permissible boundaries, which simultaneously allow a level of stability sufficient to establish and maintain chromosome-microtubule attachments and a degree of instability that permits error correction required for accurate chromosome segregation.

Figure 1

Kinetochore-microtubule stabilostat model. Kinetochore-microtubules (kMT) attachment stability is regulated in a narrow range for high fidelity chromosome segregation. Hypostable kMT attachments fails to adequately satisfy the spindle assembly checkpoint leading to mitotic delay or arrest. Hyperstable kMT attachments lose efficient error correction with the consequence being the persistence of attachment errors in anaphase and an increase in chromosome mis-segregation leading to chromosomal instability (CIN).

Figure 2

Phylogenetic comparison of kinesin-13 genes. Amino acid sequences from three kinesin-13 proteins encoded by fruit fly (Dm), mouse (Mm), and human (Hs) are compared using Clustal X. The sequence of yeast Kip3 is used as an outgroup to root the tree. Line engths are not to scale. Reprinted from Manning et al. 2007 (http://www.molbiolcell.org/content/18/8/2970)