Chromosome segregation machinery and cancer - PubMed (original) (raw)

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Chromosome segregation machinery and cancer

Kozo Tanaka et al. Cancer Sci. 2009 Jul.

Abstract

Loss or gain of chromosomes is associated with many cancer cells. This property, called chromosome instability, might arise from a lesion in the chromosome segregation machinery. Essential for chromosome segregation are the proper connection of microtubules to kinetochores, and the synchronous segregation of sister chromatids in anaphase. Accuracy of these processes is ensured by two sophisticated machineries called the correction mechanism and the spindle assembly checkpoint. Here we outline the current understanding of the underlying mechanisms, and highlight recent challenging experiments to address how chromosome segregation failure might relate to tumorigenesis. Understanding these mechanisms may lead to the discovery of new and improved anticancer therapies.

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Figures

Figure 1

Figure 1

Kinetochore–microtubule attachment. (a) Lateral versus end‐on attachment. Kinetochores are initially captured by the lattice of microtubules (lateral attachment; left) and are subsequently tethered at the end of microtubules (end‐on attachment; right). In both cases, kinetochores are transported toward a spindle pole (arrows). (b) Kinetochore–microtubule attachment in budding yeast. The Ndc80 complex is at the interface of the kinetochore–microtubule interaction, whereas the Dam1 complex is involved in poleward kinetochore motion during end‐on attachment. (c) Kinetochore–microtubule attachment in metazoans. Correlation between the structures found in electron microscopy (upper right panel) and the kinetochore structure defined at the molecular level (lower panel) has not been precisely determined yet. Molecules involved in the chromosome segregation machinery are shown schematically. Note that spindle assembly checkpoint components (Mad1, Mad2, Bub1, BubR1, and Bub3) are delocalized from kinetochores when proper kinetochore–microtubule attachment is established. Bub, budding uninhibited by benzimidazole; BubR1, Bub1‐related 1; CENP‐E, centromere protein E; Dam, Duo1 and Mps1‐interacting; KNL, kinetochore‐null; Mad, mitotic arrest‐deficient; Mis, minichromosome instability; Ndc, nuclear division cycle; RZZ; Rod, ZW10, and ZWILCH; Zwint ZW10 interactor.

Figure 2

Figure 2

How chromosomes bi‐orient on the mitotic spindle. As the capture of kinetochores by microtubules is a stochastic process, wrong orientations, termed syntelic or merotelic attachments, can occur. Because the correction mechanism is mediated by Aurora B, inhibition of this kinase results in an increased frequency of these erroneous attachments.

Figure 3

Figure 3

Interaction of microtubule plus‐ends with the kinetochore outer plate. (a) The fibrous network structure of the kinetochore outer plate, as revealed by electron tomography.( 10 ) The microtubule ends appear to be embedded in this fibrous network, and some of the fibers extend out from the plate and physically contact the microtubule wall. (Adapted by permission from Macmillan Publishers: McEwen et al. 2007 Nat. Cell Biol. 9: 516–522, copyright 2007.) (b) A cartoon illustrating how dynamic binding of kinetochores and microtubules are regulated. The affinity between fibrous structures of the outer plate (denoted by hands), and the microtubule (pole), is controlled by Aurora B‐mediated phosphorylation of the outer‐plate fibers.

Figure 4

Figure 4

Molecular basis of the SAC. (a) The SAC ‘wait anaphase’ signal is generated at unattached kinetochores. By contacting the unattached kinetochores, Mad2 molecules become active (denoted by a color change from light to dark red), eventually leading to APC/C inhibition. (b) Two different conformations of Mad2 are shown in dark and light red circles. Most of the cytoplamic, free Mad2 (light red) is converted to an alternative conformer that can bind Cdc20 (dark red). The template model predicts that the Mad1–Mad2 complex at unattached kinetochores as well as the Cdc20–Mad2 complex can both catalyze this conformational change. (c) Cdc20 is handed over from Mad2 to the Bub1‐related 1 BubR1‐Bub3 complex. BubR1 inhibits APC/C activity by acting as a psuedosubstrate, and/or by mediating Cdc20 ubiquitination and degradation (as denoted by the dotted arrows).( 48 ) It is not entirely clear when the APC/C recruits Cdc20 in this cascade.

Figure 5

Figure 5

Kinetochore stretching inactivates the SAC. (A) SAC inactivation depends on kinetochore stretching rather than the tension‐induced stretch of centromeres between sister kinetochores. When tension is low, the microtubule attachment sites (i.e. kinetochores) position close to Aurora B‐enriched centromeres where microtubule‐releasing activity is thought to be high. (B) A cartoon modeling how the metaphase‐to‐anaphase transition is controlled. (a) As a locomotive travels from metaphase to anaphase, the presence of unattached kinetochores sustains the canonical SAC pathway and generates a strong ‘wait anaphase’ signal (red light). (b) After microtubule attachment is fulfilled (green light), kinetochore stretching (denoted by a pump inside the engine) facilitates inactivation of SAC (i.e. activation of the anaphase‐promoting complex or cyclosome) throughout the metaphase‐to‐anaphase transition. (c) But if kinetochore stretching is perturbed the locomotive does not move forward because there is no pumping in the engine.

Figure 6

Figure 6

Mitotic regulation and cancer. (a) A model for how mitotic dysregulation could promote tumorigenesis. (b) Possible outcomes for the cell following treatment with antimitotic drugs. SAC, spindle assembly checkpoint.

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