New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 231

3.5. BubR1, Bub1, and Mad3: Evolutionary considerations
The confusing evolutionary relationship between yeast SAC proteins Bub1
and Mad3 on the one hand and metazoan Bub1 and BubR1 on the other led
to nomenclature (and semantic) problems almost from the beginning ( Cahill
et al., 1998; Taylor et al., 1998 ). In Drosophila , for example, the first article
describing the phenotype of “Bub1,” in fact, was actually describing BubR1
( Basu et al., 1998 ). The entry in the NCBI protein database says it all:
BubR1's official name of record is “Mitotic checkpoint serine/threonine-
protein kinase BUB1b; AltName: Full MAD3/BUB1-related protein

kinase Mad3L.” The basic problem arose because most metazoan genomes
encode two proteins related to the yeast Bub1 kinase, one of which addi-
tionally has a domain with homology to Mad3, and most crucially contains
the KEN box required for binding to Cdc20 (see Section 4.2 ).
A recent analysis ( Suijkerbuijk et al., 2012a ) has provided a compelling
narrative explaining the confusing evolutionary relationship of these three
proteins. The authors suggest that the last eukaryotic common ancestor pos-
sessed a protein they call MAD-BUB that provided the activities currently
associated with Mad3 and Bub1 in Saccharomyces cerevisiae . This ancestral
gene was duplicated in at least nine different eukaryotic lineages, and in each
case, the functions of the two paralogs subsequently diverged, with one
retaining the Mad3-like activity (with the KEN boxes to interact with
Cdc20 and inhibit the APC/C) and other retaining the Bub1-like activity
(including the kinase).
The kinase domain of the Mad3-like paralog was in most instances either
lost (yeast, worms) or modified to the point where it no longer possessed an
important kinase activity (vertebrates). The authors provide evidence that,
in mammalian cells, the activity of kinase domain is dispensable for normal
mitosis. One exception is Drosophila in which the kinase domain appears to
be intact and still contributes to mitotic function ( Rahmani et al., 2009;
Suijkerbuijk et al., 2012a ).

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4. BubR1 DURING MITOSIS
4.1. Recruitment to kinetochores
4.1.1 Cell biological aspects
BubR1 is a cytoplasmic protein during interphase ( Buffin et al., 2005; Howell
et al., 2004 ). In some cell types, it can first be detected on kinetochores dur-
ing prophase ( Buffin et al., 2005; Chan et al., 1998; Jablonski et al., 1998;