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Nat Cell Biol. 2011 Apr;13(4):475-82. doi: 10.1038/ncb2223. Epub 2011 Mar 13.

Constitutive Mad1 targeting to kinetochores uncouples checkpoint signalling from chromosome biorientation.

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  • 1Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, New York 10065, USA.

Erratum in

  • Nat Cell Biol. 2011 May;13(5):633.

Abstract

Accurate chromosome segregation depends on biorientation, whereby sister chromatids attach to microtubules from opposite spindle poles. The spindle-assembly checkpoint is a surveillance mechanism in eukaryotes that inhibits anaphase until all chromosomes have bioriented. In present models, the recruitment of the spindle-assembly checkpoint protein Mad2, through Mad1, to non-bioriented kinetochores is needed to stop cell-cycle progression. However, it is unknown whether Mad1-Mad2 targeting to kinetochores is sufficient to block anaphase. Furthermore, it is unclear whether regulators of biorientation (for example, Aurora kinases) have checkpoint functions downstream of Mad1-Mad2 recruitment or whether they act upstream to quench the primary error signal. Here, we engineered a Mad1 construct that localizes to bioriented kinetochores. We show that the kinetochore localization of Mad1 is sufficient for a metaphase arrest that depends on Mad1-Mad2 binding. By uncoupling the checkpoint from its primary error signal, we show that Aurora, Mps1 and BubR1 kinases, but not Polo-like kinase, are needed to maintain checkpoint arrest when Mad1 is present on kinetochores. Together, our data suggest a model in which the biorientation errors, which recruit Mad1-Mad2 to kinetochores, may be signalled not only through Mad2 template dynamics, but also through the activity of widely conserved kinases, to ensure the fidelity of cell division.

© 2011 Macmillan Publishers Limited. All rights reserved

PMID:
21394085
[PubMed - indexed for MEDLINE]
PMCID:
PMC3076698
Free PMC Article

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