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Review
. 2015 Feb;25(2):65-73.
doi: 10.1016/j.tcb.2014.10.002. Epub 2014 Nov 7.

Centrosome dynamics as a source of chromosomal instability

Hyun-Ja Nam  1 , Ryan M Naylor  2 , Jan M van Deursen  3
Affiliations
Review

Centrosome dynamics as a source of chromosomal instability

Hyun-Ja Nam et al. Trends Cell Biol. 2015 Feb.

Abstract

Accurate segregation of duplicated chromosomes between two daughter cells depends on bipolar spindle formation, a metaphase state in which sister kinetochores are attached to microtubules emanating from opposite spindle poles. To ensure bi-orientation, cells possess surveillance systems that safeguard against microtubule-kinetochore attachment defects, including the spindle assembly checkpoint and the error correction machinery. However, recent developments have identified centrosome dynamics--that is, centrosome disjunction and poleward movement of duplicated centrosomes--as a central target for deregulation of bi-orientation in cancer cells. In this review, we discuss novel insights into the mechanisms that underlie centrosome dynamics and discuss how these mechanisms are perturbed in cancer cells to drive chromosome mis-segregation and advance neoplastic transformation.

Keywords: cancer; centrosome disjunction; centrosome dynamics; centrosome movement; chromosomal instability.

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Figures

Figure 1
Figure 1. Centrosome dynamics
Centrosome separation occurs in two parts from late G2 through mitosis: disengagement and movement. (A) Hypothetical model for centrosome disjunction. Centrosome-associated cyclin B2/Cdk1 acts to initiate centrosome disjunction through phosphorylation of Aurora A, which in turn phosphorylates Plk1. Activated Plk1, phosphorylates Sav1-bound Mst2, triggering Mst2-mediated phosphorylation of Nek2A. Activated Nek2A phosphorylates the centrosome linker proteins C-Nap1 and rootletin, causing the physical separation of sister centrosomes. PPlγ antagonizes Nek2A phosphorylation of C-Nap1 and Rootletin. [13, 52, 57]. (B) Model for centrosome movement. Plk1 targets Eg5 to centrosomes through sequential phosphorylation of Nek9 and Nek6/7. Cdk1 has also been proposed to be important for Eg5 activation and binding to microtubules [13, 57, 63, 93].
Figure 2
Figure 2. Motor proteins forces drive poleward movement of duplicated centrosomes
Separated centrosomes move toward their respective anchoring sites with the help of multiple motor proteins, including Eg5 and dynein. Eg5 is a plus-end-directed motor protein that generates an outward pushing force between the centrosome pair [62]. Cortical and nuclear envelope associated dynein pull centrosomes apart through minus-end-directed force [94, 95].
Figure 3
Figure 3. Hypothetical mechanisms by which aberrant centrosome dynamics promote merotely and chromosome lagging
Normal centrosome dynamics promote amphitelic attachments and faithful chromosome segregation between daughter cells. Delayed centrosome disengagement promotes merotelic attachments in early prometaphase because kinetochores are accessible to microtubules from spindle poles in close proximity. At this stage, immature kinetochores have not yet recruited all of the proteins necessary for proper kinetochore-microtubule attachments, increasing the likelihood of merotelic attachments and/or decreasing the efficiency at which merotelic attachments are detected and resolved. Alternatively, delayed centrosome disengagement is associated with spindle asymmetry in metaphase, which may also promote misattachments prior to anaphase. Accelerated centrosome disengagement may promote merotelic attachments in early prometaphase again through a combination of suboptimal microtubule approach angle to the kinetochore and immature kinetochores that cannot detect and/or resolve merotelic attachments. Like delayed disengagement, accelerated centrosome disengagement has been associated with spindle asymmetry in metaphase, which is likely to promote merotelic attachments just prior to anaphase onset. Unresolved merotelic attachments resolve in chromosome lagging. MT; microtubule. KT; kinetochore.
Figure 4
Figure 4. Improper anchoring of astral microtubules at cell cortex as a source of spindle geometry defects
In cells with normal spindle geometry (left), dynein/dynactin interacts with the Gαi-LGN-NuMA anchor protein complex [89] and captures astral microtubules near the cortex contributing to symmetrical spindle pole orientation and proper kinetochore-microtubule attachment. In cells with abnormal spindle geometry, demarcation of cortical anchoring regions is not symmetrical, resulting in improper kinetochore-microtubule attachment (right).
Figure 5
Figure 5. Cancer-associated molecular drivers of abnormal centrosome dynamics
Usp44 knockout and cyclin B2 overexpression cause spontaneous tumors in mice and feature delayed and accelerated centrosome separation, respectively [4, 5]. p53 inactivation also causes abnormal centrosome disjunction and is the most commonly mutated tumor suppressor in human cancers. It is likely that there are many other proteins, such as the CIN70 gene Nek2A [96], that regulate centrosome disjunction that, when altered, promote CIN and may be associated with cancer. Likewise, abnormal centrosome movement, as is the case for Eg5 overexpression, is tightly associated with CIN and tumorigenesis. There remains a critical need to identify other cancer-associated genes that normally regulate centrosome dynamics.
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