New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 249

defect in sister chromatid cohesion in anaphase I ( Malmanche et al., 2007 ).
More specifically, sister chromatids fell apart too early, and even though
bivalent chromosomes segregated correctly in meiosis I, the centromeric
cohesion that should have held sisters together until meiosis II was removed
precociously, leading to segregation defects in meiosis II. The amino acid
substitution in BubR1 D1326N is at a conserved residue of the kinase domain,
and thus may influence its kinase activity, although this was not directly
tested. This mutant allele of BubR1 was also shown to affect the mainte-
nance of the SC in females. The SC assembled correctly, but prematurely
disassembled again later in prophase. BubR1 might therefore be required
for correct regulation of cohesin removal in meiosis I, through its role in
maintaining a component of the SC in the centromeric region after disas-
sembly of the SC in females.
There is no recombination in Drosophila males, and no SC forms in male
meiosis, even though homologues still must pair. The fact that BubR1 D1326N
perturbs chromosome segregation in both male and female meiosis suggests
that BubR1 must somehow be regulating cohesin removal in males in a
manner independent of the SC. Overall, these data suggest that BubR1 is
implicated in the maintenance of the SC and sister chromatid cohesion dur-
ing meiosis, at least in Drosophila ( Malmanche et al., 2007 ). There is no evi-
dence yet for a similar requirement for BubR1 in vertebrate meiosis.
HowBubR1 might carry out this function in promoting sister chromatid
cohesion and SCmaintenance is unknown. Perhaps, this activity is related to
the DNA repair role of BubR1 in forming the tethers that hold broken chro-
matid fragments together during mitosis ( Royou et al., 2010 ) (see
Section 5.2 ). It is noteworthy that both the cohesion activity and the teth-
ering activity seem to require an intact kinase domain (although different
mutations were tested in the two studies).
5.1.2.2 Meiotic prophase arrest
The prolonged prophase arrest prior to entry into meiosis I prometaphase is
assured by maintaining low levels of Cyclin B. In S. cerevisiae , where pro-
phase I arrest lasts at least 3.5 h, this is achieved by regulated proteolysis
of M-phase regulators by the meiosis-specific APC/C coactivator called
Ama1 ( Okaz et al., 2012; Pesin and Orr-Weaver, 2008 ). In mammalian
oocytes, no meiosis-specific activator of the APC/C has yet been identified,
and it seems instead that mitotic Cdh1 takes the role of Ama1 in prophase I
( Pesin and Orr-Weaver, 2008; Reis et al., 2006 ). Cdh1 is a member of the
Cdc20 family of APC/C regulators, and in mitosis it functions to target