New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 250

proteins for ubiquitination after the onset of anaphase. In oocytes, APC/
C-Cdh1 activity is tightly regulated in order to maintain prophase arrest by
controlling Cyclin B and Securin levels ( Marangos and Carroll, 2008;
Marangos et al., 2007 ).
Two different studies ( Homer et al., 2005; Wei et al., 2010 ) reported that
BubR1 depletion leads to premature exit from prophase and entry into mei-
osis I, and this exit correlated with a significant reduction in Cdh1 levels, and
higher levels of Cdc20 and Securin ( Homer et al., 2009 ) (Cdh1 knock-out
oocytes by contrast do not affect Securin; Holt et al., 2012 ). More Securin
would be expected to compete with Cyclin B for degradation, and so would
also increase steady-state levels of Cyclin B and hence induce entry into mei-
osis I ( Marangos and Carroll, 2008 ). Somewhat surprisingly, no increase in
Cyclin B protein levels was reported once oocytes entered meiosis. It is
therefore not clear how entry into meiosis I is induced without stabilization
of Cyclin B in BubR1 knockdown oocytes. The authors did not directly
assay overall Cdk1/Cyclin B kinase activity. It remains possible that subtle
changes in Cyclin B protein levels or kinase activity are sufficient to induce
meiotic entry. A recent study has furthermore shown that stable Cyclin A is a
strong inducer of meiotic entry ( Touati et al., 2012 ). It is not known how
turnover of Cyclin A is regulated in prophase oocytes; however, increased
Securin levels may also lead to the stabilization of Cyclin A and thereby
induce meiotic entry in these BubR1-depleted oocytes. Unexpectedly,
Cdh1 knockdown reciprocally leads to a loss of BubR1 protein levels and
once again to failure to maintain prophase arrest ( Homer et al., 2009 ).
In meiotic prophase, it is extremely important to keep the right balance
of APC/C activators and substrates to ensure proper control of entry and exit
from the meiotic cell cycle ( Okaz et al., 2012 ). BubR1 is a protein that is
regulated by multiple mitotic kinases (see Section 3 ) and functions in mitosis
in the presence of high Cdk activity, which is not the case in meiotic pro-
phase. BubR1 has not been shown to be required for mitotic entry or to
influence Cdh1 protein levels in the somatic cell cycle. Future work should
help us better understand the role of BubR1 in these oocyte-specific regu-
latory circuits in prophase I.
5.2. DNA damage response
By identifying and repairing DNA lesions, the DNA damage response
(DDR) pathway is essential for maintaining genomic stability and for cell
survival. There is increasing evidence of cross talk between the SAC and