Mechanisms of chromosome behaviour during mitosis - PubMed (original) (raw)

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Mechanisms of chromosome behaviour during mitosis

Claire E Walczak et al. Nat Rev Mol Cell Biol. 2010 Feb.

Abstract

For over a century, scientists have strived to understand the mechanisms that govern the accurate segregation of chromosomes during mitosis. The most intriguing feature of this process, which is particularly prominent in higher eukaryotes, is the complex behaviour exhibited by the chromosomes. This behaviour is based on specific and highly regulated interactions between the chromosomes and spindle microtubules. Recent discoveries, enabled by high-resolution imaging combined with the various genetic, molecular, cell biological and chemical tools, support the idea that establishing and controlling the dynamic interaction between chromosomes and microtubules is a major factor in genomic fidelity.

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Figures

Figure 1

Figure 1. Structure of the mitotic spindle

Mitosis can be staged into individual phases. In interphase, most of the chromatin is decondensed in the nucleus so that individual chromosomes cannot be seen, and the microtubules are organized in a radial array from the centrosome. During prophase, the chromosomes become highly condensed, and the centrosomes begin to separate. Nuclear envelope breakdown manifests the transition between prophase and prometaphase so that the individual chromosomes are no longer constrained in the nucleus. During prometaphase, kinetochore (k)-fibres (bundles of stabilized microtubules) connect the spindle microtubules and the kinetochores on the chromosomes, such that the chromosome can align at the spindle equator, which defines metaphase. The microtubules are uniformly oriented with their minus ends at the centrosome and their plus ends extending towards the spindle equator, where they often overlap. The astral microtubules emanate from the centrosomes and extend their plus ends towards the cell cortex. The movement of the chromosomes towards the poles occurs during anaphase A, and the two spindle poles separate during anaphase B. The nuclear envelope begins to reform and the DNA begins to decondense during telophase. An organized central spindle bundle of microtubules is also present. Cytokinesis divides the cytoplasm of the cell so that the two daughter nuclei are segregated into individual cells, which enter interphase and begin the process again.

Figure 2

Figure 2. Organization of the kinetochore–microtubule interface

a | An electron microscopy section (100 nm) of a chemically fixed PtK1 cell. The kinetochore appears as a trilaminar plate (arrow) adjacent to the chromatin. Several microtubules (arrowheads) form a prominent bundle that terminates in the kinetochore outer plate. The ends of some microtubules penetrate deeper into the chromatin (right arrowhead). b | In the ‘Hill sleeve’ model the microtubule–kinetochore interaction occurs by two distinct attachments: the links responsible for force generation connect the kinetochore with the wall of the microtubules (double arrows), and the complexes responsible for the regulation of microtubule dynamics interact directly with the tip of the microtubule (single arrows). c | An electron microscopy tomography reconstruction of the kinetochores in mammalian cells also indicates that there are two distinct attachment points: the tip of the microtubule is embedded in a radial mesh in the kinetochore outer plate (red) and a set of dense fibres extends out to bind the microtubule walls (arrow). d | In this view, a ring formed by oligomerization of Dam1 complexes encircles the end of a microtubule. The ring is capable of limited movement along the microtubule lattice but cannot easily detach from the tip of the microtubule. e | An electron microscopy tomography reconstruction of the microtubule end at the kinetochore interface, depicting a set of fibrils connecting the kinetochore to the inner surface of microtubule protofilaments. One wall of the microtubule (cyan) and the fibrils (red) are colour-traced for clarity. Image in part c is modified, with permission, from Nature Cell Biology REF. © (2007) Macmillan Publishers Ltd. All rights reserved. Image in part e is reproduced, with permission, from Cell REF. © (2008) Elsevier.

Figure 3

Figure 3. Congression models for chromosome bi-orientation

a | A mono-oriented chromosome becomes bi-oriented when a microtubule from the opposite pole is captured by a kinetochore. As the chromosome begins to congress towards the spindle equator in the direction of the dashed arrow, the leading kinetochore is associated with a thinner kinetochore (k)-fibre, whereas the trailing kinetochore is associated with a thicker k-fibre. The chromosome then becomes aligned at the spindle equator. b | Microtubules are nucleated from the k-fibre (left). These k-fibre microtubules get incorporated into the spindle proper through the action of minus end-directed motors that slide the k-fibre along spindle microtubules. c | In the traction-fibre model, the position of the chromosome is dictated by the amount of force exerted on each k-fibre (indicated by the relative sizes of the dashed arrows). The forces on each sister kinetochore are balanced at the spindle equator.

Figure 4

Figure 4. Congression models involving microtubule- and motor-based forces

a | Plus end-directed kine to chore-associated motors, such as centromere-associated protein E (CENPE), have been implicated in chromosome movement towards the spindle equator. b | Cytoplasmic dynein, a minus end-directed motor, contributes to the movement of laterally associated kinetochores towards spindle poles during early mitosis. Although only laterally attached kinetochores are depicted, dynein can also contribute to the polewards movement of chromosomes, the microtubules of which are attached in an end-on manner. c | Forces associated with polymerizing microtubules could push a chromosome towards the spindle equator during congression. d | Motors, such as KID (also known as KIF22) or other chromokinesins, associated with chromosome arms could drag a chromosome towards the spindle equator.

References

    1. Sauer G, et al. Proteome analysis of the human mitotic spindle. Mol. Cell. Proteomics. 2005;4:35–43. - PubMed
    1. Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nature Rev. Mol. Cell Biol. 2007;8:379–393. - PubMed
    1. Holland AJ, Cleveland DW. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nature Rev. Mol. Cell Biol. 2009;10:478–487. - PMC - PubMed
    1. Rajagopalan H, Lengauer C. Aneuploidy and cancer. Nature. 2004;432:338–341. - PubMed
    1. Kuriyama R, Borisy GG. Microtubule-nucleating activity of centrosomes in chinese hamster ovary cells is independent of the centriole cycle but coupled to the mitotic cycle. J. Cell Biol. 1981;91:822–826. - PMC - PubMed

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