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Kinetochore capture and bi-orientation on the mitotic spindle

Nature Reviews Molecular Cell Biology volume 6, pages 929–942 (2005)Cite this article

Key Points

  • To maintain their genetic integrity, eukaryotic cells must segregate their chromosomes accurately to opposite poles during mitosis. For high-fidelity chromosome segregation, kinetochores must be captured properly on the mitotic spindle before anaphase onset.

  • Correct kinetochore capture by spindle microtubules is achieved in a stepwise manner. Kinetochores are initially captured by the lateral surface of a single microtubule that extends from either spindle pole. Once captured, kinetochores are transported poleward along the microtubule.

  • To assure correct kinetochore capture and transport, microtubules must efficiently locate unattached kinetochores and, after capture, the kinetochores must stabilize associated microtubules.

  • Subsequently, microtubules that extend from the other spindle pole also interact with kinetochores and, eventually, each sister kinetochore attaches to microtubules that extend from opposite poles (this is known as sister kinetochore bi-orientation or amphitelic attachment). To achieve this, mal-oriented kinetochore–spindle-pole connections must be removed, and bi-orientation must be selectively promoted.

  • We discuss how kinetochores are initially captured by microtubules and how sister kinetochores subsequently bi-orient on the mitotic spindle. Although we focus mainly on recent research progress in the budding yeast Saccharomyces cerevisiae, we will also discuss findings in other organisms in this context.

Abstract

Kinetochores are large protein complexes that are formed on chromosome regions known as centromeres. For high-fidelity chromosome segregation, kinetochores must be correctly captured on the mitotic spindle before anaphase onset. During prometaphase, kinetochores are initially captured by a single microtubule that extends from a spindle pole and are then transported poleward along the microtubule. Subsequently, microtubules that extend from the other spindle pole also interact with kinetochores and, eventually, each sister kinetochore attaches to microtubules that extend from opposite poles — this is known as bi-orientation. Here we discuss the molecular mechanisms of these processes, by focusing on budding yeast and drawing comparisons with other organisms.

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Figure 1: Kinetochore–microtubule interaction in prometaphase and metaphase.
Figure 2: Modes of kinetochore–microtubule interactions.
Figure 3: Kinetochore components in budding yeast.
Figure 4: A model for kinetochore capture by microtubules in budding yeast.
Figure 5: A model for sister kinetochore bi-orientation.

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Acknowledgements

We thank N. Mukae, H. Dewar, M. van Breugel, E. K. James, A. R. Prescott, C. Antony, K. Nasmyth, N. Rachidi, C. Janke, G. Pereira, M. Galova and E. Schiebel for collaboration. Work in the authors' laboratories was supported by The Wellcome Trust, Cancer Research UK and The EMBO Young Investigator Program. We apologize to our colleagues whose work we were unable to mention in this review due to space limitations. We encourage readers to refer to the cited work using organisms other than S. cerevisiae, many of which we could not describe in detail in this review for the same reason.

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  1. School of Life Sciences, University of Dundee, Wellcome Trust Biocentre, Dow Street, Dundee, DD1 5EH, UK

    Tomoyuki U. Tanaka, Michael J. R. Stark & Kozo Tanaka

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DATABASES

Saccharomyces cerevisiae Database

Bik1

Bim1

Cac1

Cse4

Ctf19

Dam1

Glc7

Hir1

Ipl1

Kar3

Kip1

Kip2

Kip3

Mif2

Mtw1

Ndc80

Scc1

Sli15

Smy1

Spt4

Stu1

Stu2

FURTHER INFORMATION

Proteome database (registration required for access)

Kinesin homepage

School of Life Sciences, University of Dundee

Tomoyuki Tanaka's laboratory

Michael Stark's laboratory

Glossary

ANEUPLOIDY

A chromosome complement that is not a simple multiple of the haploid set.

MITOTIC SPINDLE

An intracellular apparatus that is normally made of two spindle poles, microtubules and microtubule-associated proteins. Microtubules in the mitotic spindle connect a spindle pole with the other spindle pole, chromosomes and the cell cortex. The mitotic spindle has central roles in chromosome segregation to daughter cells during cell division.

SISTER KINETOCHORE

Kinetochores are multiprotein complexes that assemble on centromeric DNA and mediate the attachment and movement of chromosomes along the microtubules of the mitotic spindle. Sister kinetochores are a pair of kinetochores that are assembled on centromeres of sister chromatids created by chromosome duplication.

SPINDLE CHECKPOINT

A surveillance mechanism that operates in mitosis to ensure that all chromosomes are correctly attached to the spindle microtubules. The spindle checkpoint senses failure in this process and delays activation of the protease separase, which cleaves a cohesin component, thereby delaying anaphase onset.

ORTHOLOGUE

A gene or a protein that belongs to different species and that has a similar nucleic-acid or amino-acid sequence, respectively.

MICROTUBULE-ORGANIZING CENTRE

(MTOC). An intracellular apparatus, such as a centrosome (metazoan) or a spindle pole body (yeast), from which microtubules grow.

DIATOMS

Single-cell algae with cell walls of silica.

KINESIN AND DYNEIN

Two different families of motor proteins. Both use the energy of ATP hydrolysis to move along a microtubule.

CHIASMATA

X-shaped connection that is formed by homologous recombination between paired homologous chromosomes during the first meiotic division.

MINICHROMOSOME

A small circular or linear artificial chromosome that has a centromere and DNA replication origin(s) (and telomeres at both ends, in the case of linear minichromosomes).

COHESIN

A multi-protein complex consisting of Smc1, Smc3, Scc1 (also known as Mcd1 or Rad21) and Scc3 (also known as Psc3 or SA1/2). This term is also used as a generic name for cohesin components. The cohesin complex is required for the establishment and maintenance of a physical link between sister chromatids.

AURORA KINASE

Member of a family of serine/threonine protein kinases that have many functions during mitosis and meiosis. Budding and fission yeasts encode a single Aurora kinase, whereas metazoan cells have two or three.

METAPHASE PLATE

Imaginary plane that lies midway between the spindle poles, perpendicular to the spindle axis. Chromosomes are positioned on this plate during metaphase in metazoan cells.

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Tanaka, T., Stark, M. & Tanaka, K. Kinetochore capture and bi-orientation on the mitotic spindle. Nat Rev Mol Cell Biol 6, 929–942 (2005). https://doi.org/10.1038/nrm1764

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