Biology Reference
In-Depth Information
Abstract
BubR1 is a critical component of the spindle assembly checkpoint, the surveillance
mechanism that helps maintain the high fidelity of mitotic chromosome segregation
by preventing cells from initiating anaphase if one or more kinetochores are not
attached to the spindle. BubR1 also helps promote the establishment of stable
kinetochore-microtubule attachments during prometaphase. In this chapter, we review
the structure, functions, and regulation of BubR1 in these
at the kinet-
ochore. We discuss its recruitment to kinetochores, its assembly into the inhibitor of
anaphase progression, and the importance of its posttranslational modifications. We
also consider the evidence for its participation in other roles beyond mitosis, such as
the meiosis-specific processes of recombination and prophase arrest of the first meiotic
division, the cellular response to DNA damage, and in the regulation of centrosome and
basal body function. Finally, studies are presented linking BubR1 dysfunction or
misregulation to aging and human disease, particularly cancer.
classical roles
1. INTRODUCTION
BubR1 is the mammalian homologue of Mad3, one of the six original
spindle assembly checkpoint (SAC) proteins identified in genetic screens in
yeast 20 years ago. The enormous attention BubR1 has received is justified
by its key role not only in the spindle checkpoint but also because it is
required for the efficient attachment of kinetochores to spindle microtu-
bules. Indeed, BubR1 was the first classical SAC protein shown to have
functions other than the SAC. But as a consequence of this intense scrutiny,
BubR1 has recently been implicated in other cellular processes as well, both
in and out of mitosis.
This review focuses primarily on mammalian BubR1, with occasional
reference to relevant studies in Drosophila BubR1 and yeast Mad3. Its basic
role in the SAC is conserved among eukaryotes and is increasingly well
understood at the molecular level. However, its contribution to various
non-SAC functions is more controversial. Its role in promoting
kinetochore-microtubule (K-MT) attachment seems widespread among
metazoans, although the molecular mechanism may vary among different
model organisms. There is far less consensus on the universality of BubR1's
other non-SAC functions among metazoans.
First, though, we briefly summarize the basic notions of mitosis, the
metaphase-anaphase transition, the SAC, and outer kinetochore structure.
For comprehensive reviews of kinetochore assembly and function and the
SAC, see DeLuca and Musacchio (2011) , Foley and Kapoor (2013) , Kops
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