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A more recent version of this article appeared on March 1, 2002
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Submitted on August 31, 2001
Revised on November 29, 2001
Accepted on December 4, 2001
1 Department of Biological Sciences, Stanford University, 385 Serra Mall, MC-5020, Stanford, CA 94305-5020
* Corresponding author. E-mail address: gwfang{at}stanford.edu.
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. We show here 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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