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Connecting up and clearing out: how kinetochore attachment silences the spindle assembly checkpoint

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Abstract

With the goal of creating two genetically identical daughter cells, cell division culminates in the equal segregation of sister chromatids. This phase of cell division is monitored by a cell cycle checkpoint known as the spindle assembly checkpoint (SAC). The SAC actively prevents chromosome segregation while one or more chromosomes, or more accurately kinetochores, remain unattached to the mitotic spindle. Such unattached kinetochores recruit SAC proteins to assemble a diffusible anaphase inhibitor. Kinetochores stop production of this inhibitor once microtubules (MTs) of the mitotic spindle are bound, but productive attachment of all kinetochores is required to satisfy the SAC, initiate anaphase, and exit from mitosis. Although mechanisms of kinetochore signaling and SAC inhibitor assembly and function have received the bulk of attention in the past two decades, recent work has focused on the principles of SAC silencing. Here, we review the mechanisms that silence SAC signaling at the kinetochore, and in particular, how attachment to spindle MTs and biorientation on the mitotic spindle may turn off inhibitor generation. Future challenges in this area are highlighted towards the goal of building a comprehensive molecular model of this process.

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Abbreviations

SAC:

Spindle assembly checkpoint

MT:

Microtubule

RZZ:

Rod/Zw10/Zwilch

CENP:

Centromere protein

KMN:

Knl1/Mis12/Ndc80 complex

CPC:

Chromosome passenger complex

TAP:

Tandem affinity purification

Cdk1:

Cyclin-dependent kinase 1

APC/C:

Anaphase promoting complex/cyclosome

MCC:

Mitotic checkpoint complex

DIC:

Dynein intermediate chain

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Acknowledgements

We apologize to the authors whose work was not discussed or cited owing to space limitations. We thank Suzanne Lens, Patrick Meraldi, Michael Lampson and the members of the Kops and Shah laboratories for their insightful comments. Work in the Kops laboratory is supported by the Dutch Cancer Society, by the Netherlands Organization for Scientific Research (NWO), and by the European Research Council (ERC). Work in the Shah laboratory is supported by the US National Institutes of Health (NIH) and the Foundation of the Beckman Laser Institute (BLI).

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Authors and Affiliations

  1. Department of Medical Oncology and Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands

    Geert J. P. L. Kops

  2. Department of Systems Biology, Harvard Medical School and Renal Division, Brigham and Women’s Hospital, Boston, MA, USA

    Jagesh V. Shah

  3. Medical Oncology & Molecular Cancer Research, University Medical Center Utrecht, Stratenum 2.231, Universiteitsweg 100, 3584, CG, Utrecht, The Netherlands

    Geert J. P. L. Kops

  4. Department of Systems Biology, Harvard Medical School, 4 Blackfan Circle, HIM 564, Boston, MA, 02115, USA

    Jagesh V. Shah

Authors
  1. Geert J. P. L. Kops
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  2. Jagesh V. Shah
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Corresponding authors

Correspondence to Geert J. P. L. Kops or Jagesh V. Shah.

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Communicated by Erich Nigg

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Kops, G.J.P.L., Shah, J.V. Connecting up and clearing out: how kinetochore attachment silences the spindle assembly checkpoint. Chromosoma 121, 509–525 (2012). https://doi.org/10.1007/s00412-012-0378-5

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  • DOI: https://doi.org/10.1007/s00412-012-0378-5

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