The spindle-assembly checkpoint in space and time View Full Text


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Article Info

DATE

2007-04-11

AUTHORS

Andrea Musacchio, Edward D. Salmon

ABSTRACT

Key PointsThe spindle-assembly checkpoint (SAC) is a safety device that monitors the attachment of spindle microtubules to the surface of chromosome-associated structures called kinetochores. It is believed that the SAC senses the occupancy of microtubules at the surface of kinetochores, as well as the accumulation of inter-kinetochore tension when sister kinetochores are linked to opposite spindle poles.The SAC is active in prometaphase during the microtubule–kinetochore attachment process, and it is downregulated when all sister chromatids have aligned to the mitotic spindle in a bipolar fashion. This triggers the loss of sister-chromatid cohesion, which initiates sister-chromatid separation at anaphase.The signalling activity of the SAC in prometaphase seems to converge on the formation of at least one SAC effector, the mitotic checkpoint complex (MCC). This complex contains the SAC proteins MAD2, BUBR1 and BUB3 bound to the SAC target CDC20. This complex inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C), which is required to remove sister-chromatid cohesion.The way the MCC is generated from its constituent subunits is the subject of controversy. Especially controversial is the relative contribution offered by the cytosol and by kinetochores to MCC formation. There is evidence from Saccharomyces cerevisiae that the MCC can form in the absence of kinetochores. On the other hand, all SAC proteins localize to kinetochores in mitosis and it seems likely that this will contribute a mass-action effect, enhancing the rate of MCC formation.A still-speculative hypothesis, the 'MAD2 template' hypothesis, proposes that the interaction of MAD2 with CDC20 follows a prion-like scenario in which an O-MAD2 conformer is primed by a kinetochore-bound C-MAD2 conformer to bind CDC20.Besides the core SAC machinery, which is represented by the MCC subunits, several auxiliary functions contribute to SAC signal amplification. These include certain kinases (BUB1, BUBR1, MPS1 and Aurora B), the microtubule motor protein centromere protein E (CENP-E), and components of the ROD–ZW10–ZWILCH (RZZ) complex. p31comet and dynein, on the other hand, contribute to the downregulation of SAC signalling.Subtle alterations of SAC function might cause aneuploidy and accelerate tumorigenesis. On the other hand, the SAC is an essential device in metazoans, and current evidence indicates that its functions are also essential for the survival of cancer cells. This points to the SAC as a possible target in cancer therapy. More... »

PAGES

379-393

References to SciGraph publications

  • 2004-02-08. Correcting improper chromosome–spindle attachments during cell division in NATURE CELL BIOLOGY
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  • 2006-04. The reversibility of mitotic exit in vertebrate cells in NATURE
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  • 2003-03-17. Human CENP-I specifies localization of CENP-F, MAD1 and MAD2 to kinetochores and is essential for mitosis in NATURE CELL BIOLOGY
  • 2000-03. Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20 in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • 2003-11. The cellular geography of Aurora kinases in NATURE REVIEWS MOLECULAR CELL BIOLOGY
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  • 2006-03-22. Phylogenetic and structural analysis of centromeric DNA and kinetochore proteins in GENOME BIOLOGY
  • 2004-03-14. The Mad2 spindle checkpoint protein has two distinct natively folded states in NATURE STRUCTURAL & MOLECULAR BIOLOGY
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  • 2005-12-04. The Ipl1-Aurora protein kinase activates the spindle checkpoint by creating unattached kinetochores in NATURE CELL BIOLOGY
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  • 2000-09-21. p55CDC/hCDC20 is associated with BUBR1 and may be a downstream target of the spindle checkpoint kinase in ONCOGENE
  • 2006-05-29. Hec1 sequentially recruits Zwint-1 and ZW10 to kinetochores for faithful chromosome segregation and spindle checkpoint control in ONCOGENE
  • 2005-10. On the road to cancer: aneuploidy and the mitotic checkpoint in NATURE REVIEWS CANCER
  • 2005-04-18. Getting in and out of mitosis with Polo-like kinase-1 in ONCOGENE
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  • 2001-10-11. Kinetochore dynein: its dynamics and role in the transport of the Rough deal checkpoint protein in NATURE CELL BIOLOGY
  • 2002-10. The spindle checkpoint: structural insights into dynamic signalling in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2006-04-16. The human CENP-A centromeric nucleosome-associated complex in NATURE CELL BIOLOGY
  • 2006-04-16. The CENP-H–I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres in NATURE CELL BIOLOGY
  • Journal

    TITLE

    Nature Reviews Molecular Cell Biology

    ISSUE

    5

    VOLUME

    8

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nrm2163

    DOI

    http://dx.doi.org/10.1038/nrm2163

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/17426725


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    43 schema:description Key PointsThe spindle-assembly checkpoint (SAC) is a safety device that monitors the attachment of spindle microtubules to the surface of chromosome-associated structures called kinetochores. It is believed that the SAC senses the occupancy of microtubules at the surface of kinetochores, as well as the accumulation of inter-kinetochore tension when sister kinetochores are linked to opposite spindle poles.The SAC is active in prometaphase during the microtubule–kinetochore attachment process, and it is downregulated when all sister chromatids have aligned to the mitotic spindle in a bipolar fashion. This triggers the loss of sister-chromatid cohesion, which initiates sister-chromatid separation at anaphase.The signalling activity of the SAC in prometaphase seems to converge on the formation of at least one SAC effector, the mitotic checkpoint complex (MCC). This complex contains the SAC proteins MAD2, BUBR1 and BUB3 bound to the SAC target CDC20. This complex inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C), which is required to remove sister-chromatid cohesion.The way the MCC is generated from its constituent subunits is the subject of controversy. Especially controversial is the relative contribution offered by the cytosol and by kinetochores to MCC formation. There is evidence from Saccharomyces cerevisiae that the MCC can form in the absence of kinetochores. On the other hand, all SAC proteins localize to kinetochores in mitosis and it seems likely that this will contribute a mass-action effect, enhancing the rate of MCC formation.A still-speculative hypothesis, the 'MAD2 template' hypothesis, proposes that the interaction of MAD2 with CDC20 follows a prion-like scenario in which an O-MAD2 conformer is primed by a kinetochore-bound C-MAD2 conformer to bind CDC20.Besides the core SAC machinery, which is represented by the MCC subunits, several auxiliary functions contribute to SAC signal amplification. These include certain kinases (BUB1, BUBR1, MPS1 and Aurora B), the microtubule motor protein centromere protein E (CENP-E), and components of the ROD–ZW10–ZWILCH (RZZ) complex. p31comet and dynein, on the other hand, contribute to the downregulation of SAC signalling.Subtle alterations of SAC function might cause aneuploidy and accelerate tumorigenesis. On the other hand, the SAC is an essential device in metazoans, and current evidence indicates that its functions are also essential for the survival of cancer cells. This points to the SAC as a possible target in cancer therapy.
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