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J. Cell Biol.,
Volume 142, Number 1, July 13, 1998 1-11
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
A feedback control mechanism, or cell cycle
checkpoint, delays the onset of anaphase until all the
chromosomes are correctly aligned on the mitotic spindle. Previously, we showed that the murine homologue
of Bub1 is not only required for checkpoint response to
spindle damage, but also restrains progression through
a normal mitosis (Taylor, S.S., and F. McKeon. 1997. Cell. 89:727-735). Here, we describe the identification
of a human homologue of Bub3, a 37-kD protein with
four WD repeats. Like Bub1, Bub3 localizes to kinetochores before chromosome alignment. In addition,
Bub3 and Bub1 interact in mammalian cells. Deletion
mapping was used to identify the domain of Bub1 required for binding Bub3. Significantly, this same domain is required for kinetochore localization of Bub1, suggesting that the role of Bub3 is to localize Bub1 to
the kinetochore, thereby activating the checkpoint in
response to unattached kinetochores. The identification of a human Mad3/Bub1-related protein kinase, hBubR1, which can also bind Bub3 in mammalian cells,
is described. Ectopically expressed hBubR1 also localizes to kinetochores during prometaphase, but only
when hBub3 is overexpressed. We discuss the implications of the common interaction between Bub1 and
hBubR1 with hBub3 for checkpoint control.
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