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Vol. 13, Issue 9, 3029-3041, September 2002
*McKusick-Nathans Institute of Genetic Medicine,
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 Saccharomyces cerevisiae. Loss of Bub1 or
Bub3 protein elicits the largest effect. Analysis of Bub1p reveals the
presence of two molecular functions. An N-terminal 608-amino acid
(nonkinase) 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 Bub3p binding and in kinetochore localization
by one-hybrid assay. An adjacent segment is required for Mad1p binding,
detected by deletion analysis and coimmunoprecipitation. 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 through introduction of
kinetochore or spindle damage.
Predoctoral Training Program in Human Genetics and
Molecular Biology, and Department of Molecular Biology
and Genetics, Johns Hopkins University School of Medicine, Baltimore,
Maryland 21205; and §Wellcome Trust Centre for Cell
Biology, Institute of Cell and Molecular Biology, University of
Edinburgh, Edinburgh, United Kingdom
Corresponding author. E-mail address:
fspencer{at}jhmi.edu.
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