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Vol. 13, Issue 3, 755-766, March 2002
Department of Biological Sciences, Stanford University, Stanford,
California 94305-5020
The spindle assembly checkpoint monitors the attachment of
kinetochores to the mitotic spindle and the tension exerted
on kinetochores by microtubules and delays the onset of
anaphase until all the chromosomes are aligned at the metaphase plate. The target of the checkpoint control is the anaphase-promoting complex
(APC)/cyclosome, a ubiquitin ligase whose activation by Cdc20 is
required for separation of sister chromatids. In response to activation
of the checkpoint, Mad2 binds to and inhibits Cdc20-APC. I show herein
that in checkpoint-arrested cells, human Cdc20 forms two separate,
inactive complexes, a lower affinity complex with Mad2 and a higher
affinity complex with BubR1. Purified BubR1 binds to recombinant Cdc20
and this interaction is direct. Binding of BubR1 to Cdc20 inhibits
activation of APC and this inhibition is independent of its kinase
activity. Quantitative analysis indicates that BubR1 is 12-fold more
potent than Mad2 as an inhibitor of Cdc20. Although at high protein
concentrations BubR1 and Mad2 each is sufficient to inhibit Cdc20,
BubR1 and Mad2 mutually promote each other's binding to Cdc20 and
function synergistically at physiological concentrations to
quantitatively inhibit Cdc20-APC. Thus, BubR1 and Mad2 act
cooperatively to prevent premature separation of sister chromatids by
directly inhibiting APC.
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