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The life and miracles of kinetochores.

Santaguida S, Musacchio A - EMBO J. (2009)

Bottom Line: The main functions of kinetochores can be grouped under four modules.The first module, in the inner kinetochore, contributes a sturdy interface with centromeric chromatin.The second module, the outer kinetochore, contributes a microtubule-binding interface.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.

ABSTRACT
Kinetochores are large protein assemblies built on chromosomal loci named centromeres. The main functions of kinetochores can be grouped under four modules. The first module, in the inner kinetochore, contributes a sturdy interface with centromeric chromatin. The second module, the outer kinetochore, contributes a microtubule-binding interface. The third module, the spindle assembly checkpoint, is a feedback control mechanism that monitors the state of kinetochore-microtubule attachment to control the progression of the cell cycle. The fourth module discerns correct from improper attachments, preventing the stabilization of the latter and allowing the selective stabilization of the former. In this review, we discuss how the molecular organization of the four modules allows a dynamic integration of kinetochore-microtubule attachment with the prevention of chromosome segregation errors and cell-cycle progression.

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Related in: MedlinePlus

Error correction and the spindle checkpoint. (A) Schematic description of the geometry of the centromere–kinetochore interface in the absence and presence of tension. (B) The boxed area in (A) enlarged. Phosphorylation of certain substrates at the centromere–kinetochore interface is constitutive (the yellow circle marked by ‘P'), that is the substrate is phosphorylated with or without tension. Other substrates are only phosphorylated in the absence of tension, because their separation from the centromere exceeds a threshold value when tension is present. (C) Left: schematic description of the CPC complex. Right: the CPC occupies the centromere, and only a subset of complexes is located near the centromere–kinetochore interface. (D) A comprehensive model of checkpoint control and error correction. In the absence of tension, either substrate like Ndc80 become phosphorylated by Aurora B or by other kinases whose activation requires Aurora B. This creates a condition for SAC activation through the recruitment of SAC proteins (Ditchfield et al, 2003; Hauf et al, 2003). On the other hand, the phosphorylation of Ndc80 decreases the binding affinity for microtubules (Cheeseman et al, 2006; DeLuca et al, 2006; Ciferri et al, 2008). This creates a state of labile attachment that will become corrected unless a force is applied. The removal of Ndc80 and possibly other substrates from the reach of Aurora B stabilizes the attachment through the action of a phosphatase.
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f9: Error correction and the spindle checkpoint. (A) Schematic description of the geometry of the centromere–kinetochore interface in the absence and presence of tension. (B) The boxed area in (A) enlarged. Phosphorylation of certain substrates at the centromere–kinetochore interface is constitutive (the yellow circle marked by ‘P'), that is the substrate is phosphorylated with or without tension. Other substrates are only phosphorylated in the absence of tension, because their separation from the centromere exceeds a threshold value when tension is present. (C) Left: schematic description of the CPC complex. Right: the CPC occupies the centromere, and only a subset of complexes is located near the centromere–kinetochore interface. (D) A comprehensive model of checkpoint control and error correction. In the absence of tension, either substrate like Ndc80 become phosphorylated by Aurora B or by other kinases whose activation requires Aurora B. This creates a condition for SAC activation through the recruitment of SAC proteins (Ditchfield et al, 2003; Hauf et al, 2003). On the other hand, the phosphorylation of Ndc80 decreases the binding affinity for microtubules (Cheeseman et al, 2006; DeLuca et al, 2006; Ciferri et al, 2008). This creates a state of labile attachment that will become corrected unless a force is applied. The removal of Ndc80 and possibly other substrates from the reach of Aurora B stabilizes the attachment through the action of a phosphatase.

Mentions: How does Aurora B distinguish correct from incorrect attachments? How is its activity differentially regulated at correct and incorrect attachments? Bi-oriented sister chromatids are under tension, that is they experience a force that tends to part the sisters, stretching centromeric chromatin as well as the kinetochore (Skibbens et al, 1993; Waters et al, 1996; Maresca and Salmon, 2009; Uchida et al, 2009). Incompletely (monotelic or even unbound) or incorrectly (syntelic) attached sisters, on the other hand, are not under tension (e.g. Ditchfield et al, 2003; Liu et al, 2009). As (1) the distance between centromeres and kinetochores increases when the sisters are under tension, and (2) the CPC is located at the centromere, it was proposed that the ability of Ipl1/Aurora B to reach its substrates in the kinetochore may be reduced or eliminated when tension builds up (Figure 9A and B) (Tanaka et al, 2002). Recently, this hypothesis was corroborated by elegant experiments in which an Aurora B substrate docked within the kinetochore at a sufficiently large distance from the centromere became dephosphorylated as microtubule attachment ensued (Liu et al, 2009). Substrates closer to the centromere, on the other hand, were constitutively phosphorylated with or without microtubule attachment. Overall, these results suggest that Aurora B delivers constitutive levels of phosphorylation during the attachment phase, and that the regulation of attachment depends on the accessibility of the substrates (Figure 9B) (Liu et al, 2009).


The life and miracles of kinetochores.

Santaguida S, Musacchio A - EMBO J. (2009)

Error correction and the spindle checkpoint. (A) Schematic description of the geometry of the centromere–kinetochore interface in the absence and presence of tension. (B) The boxed area in (A) enlarged. Phosphorylation of certain substrates at the centromere–kinetochore interface is constitutive (the yellow circle marked by ‘P'), that is the substrate is phosphorylated with or without tension. Other substrates are only phosphorylated in the absence of tension, because their separation from the centromere exceeds a threshold value when tension is present. (C) Left: schematic description of the CPC complex. Right: the CPC occupies the centromere, and only a subset of complexes is located near the centromere–kinetochore interface. (D) A comprehensive model of checkpoint control and error correction. In the absence of tension, either substrate like Ndc80 become phosphorylated by Aurora B or by other kinases whose activation requires Aurora B. This creates a condition for SAC activation through the recruitment of SAC proteins (Ditchfield et al, 2003; Hauf et al, 2003). On the other hand, the phosphorylation of Ndc80 decreases the binding affinity for microtubules (Cheeseman et al, 2006; DeLuca et al, 2006; Ciferri et al, 2008). This creates a state of labile attachment that will become corrected unless a force is applied. The removal of Ndc80 and possibly other substrates from the reach of Aurora B stabilizes the attachment through the action of a phosphatase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2722247&req=5

f9: Error correction and the spindle checkpoint. (A) Schematic description of the geometry of the centromere–kinetochore interface in the absence and presence of tension. (B) The boxed area in (A) enlarged. Phosphorylation of certain substrates at the centromere–kinetochore interface is constitutive (the yellow circle marked by ‘P'), that is the substrate is phosphorylated with or without tension. Other substrates are only phosphorylated in the absence of tension, because their separation from the centromere exceeds a threshold value when tension is present. (C) Left: schematic description of the CPC complex. Right: the CPC occupies the centromere, and only a subset of complexes is located near the centromere–kinetochore interface. (D) A comprehensive model of checkpoint control and error correction. In the absence of tension, either substrate like Ndc80 become phosphorylated by Aurora B or by other kinases whose activation requires Aurora B. This creates a condition for SAC activation through the recruitment of SAC proteins (Ditchfield et al, 2003; Hauf et al, 2003). On the other hand, the phosphorylation of Ndc80 decreases the binding affinity for microtubules (Cheeseman et al, 2006; DeLuca et al, 2006; Ciferri et al, 2008). This creates a state of labile attachment that will become corrected unless a force is applied. The removal of Ndc80 and possibly other substrates from the reach of Aurora B stabilizes the attachment through the action of a phosphatase.
Mentions: How does Aurora B distinguish correct from incorrect attachments? How is its activity differentially regulated at correct and incorrect attachments? Bi-oriented sister chromatids are under tension, that is they experience a force that tends to part the sisters, stretching centromeric chromatin as well as the kinetochore (Skibbens et al, 1993; Waters et al, 1996; Maresca and Salmon, 2009; Uchida et al, 2009). Incompletely (monotelic or even unbound) or incorrectly (syntelic) attached sisters, on the other hand, are not under tension (e.g. Ditchfield et al, 2003; Liu et al, 2009). As (1) the distance between centromeres and kinetochores increases when the sisters are under tension, and (2) the CPC is located at the centromere, it was proposed that the ability of Ipl1/Aurora B to reach its substrates in the kinetochore may be reduced or eliminated when tension builds up (Figure 9A and B) (Tanaka et al, 2002). Recently, this hypothesis was corroborated by elegant experiments in which an Aurora B substrate docked within the kinetochore at a sufficiently large distance from the centromere became dephosphorylated as microtubule attachment ensued (Liu et al, 2009). Substrates closer to the centromere, on the other hand, were constitutively phosphorylated with or without microtubule attachment. Overall, these results suggest that Aurora B delivers constitutive levels of phosphorylation during the attachment phase, and that the regulation of attachment depends on the accessibility of the substrates (Figure 9B) (Liu et al, 2009).

Bottom Line: The main functions of kinetochores can be grouped under four modules.The first module, in the inner kinetochore, contributes a sturdy interface with centromeric chromatin.The second module, the outer kinetochore, contributes a microtubule-binding interface.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.

ABSTRACT
Kinetochores are large protein assemblies built on chromosomal loci named centromeres. The main functions of kinetochores can be grouped under four modules. The first module, in the inner kinetochore, contributes a sturdy interface with centromeric chromatin. The second module, the outer kinetochore, contributes a microtubule-binding interface. The third module, the spindle assembly checkpoint, is a feedback control mechanism that monitors the state of kinetochore-microtubule attachment to control the progression of the cell cycle. The fourth module discerns correct from improper attachments, preventing the stabilization of the latter and allowing the selective stabilization of the former. In this review, we discuss how the molecular organization of the four modules allows a dynamic integration of kinetochore-microtubule attachment with the prevention of chromosome segregation errors and cell-cycle progression.

Show MeSH
Related in: MedlinePlus