BubR1 is essential for kinetochore localization of other spindle checkpoint proteins and its phosphorylation requires Mad1

doi:10.1083/jcb.200204048

Published 5 August 2002. doi:10.1083/jcb.200204048

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© The Rockefeller University Press, 0021-9525/2002/8/487 $5.00
The Journal of Cell Biology, Volume 158, Number 3, August 5, 2002 487-496

Article

BubR1 is essential for kinetochore localization of other spindle checkpoint proteins and its phosphorylation requires Mad1

Rey-Huei Chen

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853

Address correspondence to R.-H. Chen, Department of Molecular Biology and Genetics, 258 Biotechnology Building, Cornell University, Ithaca, NY 14853. Tel.: (607) 255-0518. Fax: (607) 255-6249. E-mail: rc70{at}cornell.edu

The spindle checkpoint delays anaphase onset until all chromosomeshave attached properly to the mitotic spindle. Checkpoint signalis generated at kinetochores that are not bound with spindlemicrotubules or not under tension. Unattached kinetochores associatewith several checkpoint proteins, including BubR1, Bub1, Bub3,Mad1, Mad2, and CENP-E. I herein show that BubR1 is importantfor the spindle checkpoint in Xenopus egg extracts. The proteinaccumulates and becomes hyperphosphorylated at unattached kinetochores.Immunodepletion of BubR1 greatly reduces kinetochore bindingof Bub1, Bub3, Mad1, Mad2, and CENP-E. Loss of BubR1 also impairsthe interaction between Mad2, Bub3, and Cdc20, an anaphase activator.These defects are rescued by wild-type, kinase-dead, or a truncatedBubR1 that lacks its kinase domain, indicating that the kinaseactivity of BubR1 is not essential for the spindle checkpointin egg extracts. Furthermore, localization and hyperphosphorylationof BubR1 at kinetochores are dependent on Bub1 and Mad1, butnot Mad2. This paper demonstrates that BubR1 plays an importantrole in kinetochore association of other spindle checkpointproteins and that Mad1 facilitates BubR1 hyperphosphorylationat kinetochores.

Key Words: spindle checkpoint; Xenopus; BubR1; Mad1; Bub1

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