Abstract
The accurate segregation of chromosomes is essential for the survival of organisms and cells. Mistakes can lead to aneuploidy, tumorigenesis and congenital birth defects. The spindle assembly checkpoint ensures that chromosomes properly align on the spindle, with sister chromatids attached to microtubules from opposite poles. Here, we review how tension is used to identify and selectively destabilize incorrect attachments, and thus serves as a trigger of the spindle assembly checkpoint to ensure fidelity in chromosome segregation. Tension is generated on properly attached chromosomes as sister chromatids are pulled in opposing directions but resisted by centromeric cohesin. We discuss the role of the Aurora B kinase in tension-sensing and explore the current models for translating mechanical force into Aurora B-mediated biochemical signals that regulate correction of chromosome attachments to the spindle.
Highlights
Sensing Mechanisms in the Organisms package their genetic material into chromosomes; faithful segregation of these structures through cell division is critical as mistakes can lead to disease, infertility and congenital defects [1,2]
Many models have been proposed to explain the Aurora B-based translation of mechanical tension into biochemical signaling, and they generally group into three categories: (1) spatial separation models, where Aurora B is physically separated from its targets by tension, (2) tension-sensitive activation models, where the activity of Aurora B is modulated by another protein in response to tension, and (3) kinetochore localization models, where a subpopulation of Aurora B localizes on kinetochores in early mitosis when tension is low, and (4) a new model in which the downstream effects of Aurora B phosphorylation are differentiated by tension rather initial sensing by the kinase
Truncations of INCENP in human cells reduces the phosphorylation of outer kinetochore proteins Dsn1, KNL1 and Hec1 but not inner centromere protein CENP-A or chromatin [125]. These studies suggest that INCENP tethers Aurora B to a region specified by its length, and under tension, the INCENP leash prevents the kinase from reaching the outer kinetochore
Summary
Sensing Mechanisms in the Organisms package their genetic material into chromosomes; faithful segregation of these structures through cell division is critical as mistakes can lead to disease, infertility and congenital defects [1,2]. To ensure dividing cells receive equal numbers of chromosomes, sister chromatids must bi-orient with their kinetochores attached to microtubules from opposite spindle poles (Figure 1A). Incorrect kinetochores sister chromatids attached where to microtubules fromonopposite spindle poles. Single Incorrect kinetochore is attached, and merotelic (syntelic and monotelic) or improper tension (merotelic) on the chromosome. The accuracy of chromosome segregation is protected by the spindle assembly checkpoint which monitors kinetochore-microtubule and activatescheckin reThe(SAC). Debate has surrounded the SAC trigger; some argue that SAC activation is caused by lack of tension on incorrect attachments and others argue activation is caused by unattached kinetochores [11] The basis of this debate will be discussed below, but our review will focus on the role of tension in sensing and correcting improper attachments
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