Correcting aberrant kinetochore microtubule attachments: an Aurora B-centric view - PubMed (original) (raw)

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Correcting aberrant kinetochore microtubule attachments: an Aurora B-centric view

Alexander E Kelly et al. Curr Opin Cell Biol. 2009 Feb.

Abstract

The directed movement of chromosomes during mitosis and meiosis relies on microtubule-mediated connections between spindle poles and kinetochores assembled on chromosomes. The molecular basis for the dynamic interaction between microtubules and kinetochores is just beginning to be unveiled. Here, focusing on the mitotic centromere kinase Aurora B, we review our current understanding of the signaling pathways that correct erroneous microtubule attachment at kinetochores. We evaluate several potential models that may explain how maloriented attachments are recognized and processed by the Aurora B pathway.

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Figures

Figure 1

Figure 1

Classification of kinetochore microtubule attachments. Amphitelic attachment: this is the correct attachment, in which all the microtubules attached to a kinetochore connect one spindle pole, while all those attached to its sister kinetochore link to its opposite pole. Monotelic attachment: a kinetochore attaches to microtubules that link to one spindle pole, while its sister kinetochore does not attach to any microtubules. Syntelic attachment: both sister kinetochores are linked to the same pole by microtubules. Merotelic attachment: a kinetochore attaches to microtubules from more than one spindle pole, a situation that results in a lagging chromosome during anaphase. Kinetochores are in yellow, microtubules in green, chromosomes in light blue and centrosomes in orange.

Figure 2

Figure 2

Aurora B pathway control of microtubule attachment. The CPC, composed of Aurora B, INCENP, Dasra (Borealin) and Survivin, is localized to inner centromre, where it signals to correct mal-oriented kinetochore-microtubule attachments. Aurora B can be autoactivated by phosphorylation in trans, but the reaction is inhibited by phosphatases. Upon loss of tension between sister chromatids, inner centromeric Aurora B is activated, where activation may occur directly or indirectly. At the kinetochore, Aurora B phosphorylates Ndc80, leading to destabilization of microtubules at kinetochores. Lack of tension activates the Plk1 dependent phosphorylation of BubR1, a modification which is critical for microtubule attachment [62]. Once microtubule attachment is established, BubR1 is inactivated [63]. Upon bipolar attachment, the Aurora B pathway and the Polo pathway are inactivated, possibly through the action of PP1.

Figure 3

Figure 3

Three models of how the Aurora B pathway is controlled by microtubule attachment or tension. Each model is a simplified enlargement of the inter-kinetochore regions of chromosomes under tension or in a relaxed state. Kinetochores are in orange, microtubules in green, and chromosomes are in light blue. Arrows indicate activation. Model 1: Tension-regulated separation of Aurora B from its kinetochore substrates The distance between active Aurora B at inner centromeres and its kinetochore substrates increases upon bioriented attachment. This increased distance would decrease the likelihood of Aurora B binding kinetochore substrates, which is reinforced by PP1 phosphatase. Model 2: Microtubule-dependent regulation of Aurora B Inner centromeric Aurora B on misaligned chromosomes is more accessible to microtubules than at the metaphase plate. Interactions with microtubules stimulate the kinase activity of Aurora B resulting destabilized microtubule attachments. Model 3: Modulation of Aurora B activity through structural changes in centromeric chromatin Assuming that the CPC is activated by chromatin through a clustering mechanism, the lack of tension may cause a compaction of chromatin at the centromere leading to kinase activation. However, under tension, the chromatin fibers are stretched resulting in a lower effective concentration of the CPC and thus activity. Chromatin fibers are modeled as thin black lines.

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References

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