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A more recent version of this article appeared on September 1, 2002
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Submitted on November 29, 2001
Revised on June 3, 2002
Accepted on June 6, 2002
1 Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; and Predoctoral Training Program in Human Genetics and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD
2 Wellcome Trust Centre for Cell Biology, Institute of Cell and Molecular Biology, University of Edinburgh, UK
3 Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
4 Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; and Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD
* Corresponding author. E-mail address: fspencer{at}jhmi.edu.
The spindle checkpoint plays a central role in the fidelity of chromosome transmission by ensuring that anaphase is initiated only after kinetochore-microtubule associations of all sister chromatid pairs are complete. In this study, we find that known spindle checkpoint proteins do not contribute equally to chromosome segregation fidelity in budding yeast. Loss of Bub1 or Bub3 protein elicits the largest effect. Analysis of Bub1p reveals the presence of two molecular functions. An N-terminal 608aa (non-kinase) portion of the protein supports robust checkpoint activity, and, as expected, contributes to chromosome segregation. A C-terminal kinase-encoding segment independently contributes to chromosome segregation through an unknown mechanism. Both molecular functions depend on association with Bub3p. A 156 amino acid fragment of Bub1p functions in BUB3-binding and in kinetochore localization by one-hybrid assay. An adjacent segment is required for Mad1p binding, detected by deletion analysis and co- immunoprecipitation. Finally, overexpression of wild-type BUB1 or MAD3 genes leads to chromosome instability. Analysis of this activity indicates that the Bub3p-binding domain of Bub1p contributes to this phenotype, through disruption of checkpoint activity as well as introduction of kinetochore or spindle damage.
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