New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 222

the multisubunit ubiquitin E3 ligase called the anaphase-promoting
complex/cyclosome (APC/C). This enzyme ubiquitinates protein sub-
strates containing at least one of two different degenerate peptide motifs
(degrons) called the D-box and the KEN-box ( Pfleger and Kirschner,
2000 ). Once polyubiquitinated, the targeted proteins are degraded by the
26S proteasome ( Peters, 2006 ). Although many proteins with these degron
signals are degraded in the course of mitosis, prior to anaphase onset the
APC/C can ubiquitinate Cyclin B and Securin only when it is associated
with a specific coactivator called Cdc20. It is the ubiquitination of Cyclin
B and Securin by the APC/C Cdc20 that is specifically blocked by the ana-
phase inhibitor of the SAC.
Once all chromosomes are properly aligned, the SAC stops generating
the anaphase inhibitor, and the APC/C Cdc20 is free to target Cyclin
B and Securin for ubiquitination and degradation ( Clute and Pines,
1999 ). With Securin gone, separase can cleave the cohesins binding the sister
chromatids, and the spindle can then pull them to opposite poles. Mean-
while, with the degradation of Cyclin B, the cell can revert to the physio-
logical state of interphase. At the molecular level, the anaphase inhibitor is
called the mitotic checkpoint complex (MCC), composed of Cdc20 itself
and the SAC proteins Mad2, BubR1, and Bub3 ( Chen, 2002; Musacchio
and Salmon, 2007; Sudakin et al., 2001 ). A similar MCC has been identified
in yeast ( Fraschini et al., 2001; Hardwick et al., 2000 ). Of these components,
it is the complex of Cdc20 with BubR1 that is the most critical for inhibiting
the APC/C. We will have more to say about the role of BubR1 in the MCC
later on. There is still much to learn about the regulation of MCC assembly
at unattached kinetochores and its mode of inhibition of the APC/C.
2.2. Chromosome attachment and error correction
Besides unattached kinetochores, there are other kinds of attachment errors.
The two kinetochores of a given chromosome may attach to microtubules
from the same spindle pole (syntelic attachment), or one kinetochore may
have captured microtubules emanating from both spindle poles (merotelic
attachment). These are also potential sources of segregation errors. Besides
the SAC apparatus, the centromeric kinase Aurora B plays an important role
in correcting these errors (Aurora B activity may be critical to the SAC func-
tion as well; see, e.g., Santaguida et al., 2011 ).
In general, Aurora B phosphorylation of certain kinetochore proteins
leads to the destabilization of K-MT attachments, and the subsequent