New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 221

and Shah (2012) , Lara-Gonzalez et al. (2012) , Musacchio and Salmon
(2007) , Przewloka and Glover (2009) , Santaguida and Musacchio (2009) ,
and Varma and Salmon (2012) .
2. CHROMOSOME SEGREGATION AND CELL
CYCLE MACHINERY
2.1. Mitosis, SAC, and kinetochores
During mitosis, the dividing cell must accurately distribute a complete set of
chromosomes to each of the two daughters. Missegregation of a single chro-
mosome would generate two aneuploid cells, which can have dire conse-
quences for the cells and for the organism, and if the mitotic cell is in the
germline, for the offspring of the organism as well. Broadly speaking, the
cell assures the fidelity of chromosome transmission during mitosis by using
both a mechanical process and a quality control process. The mechanical
process involves a robust mechanism for promoting the capture of kineto-
chores by the spindle microtubules and orientation of chromosomes at the
spindle equator. Because the encounter between the kinetochores and the
spindle microtubules has a stochastic component, a cell cannot tell precisely
how long it will take for all kinetochores to properly attach to the spindle.
This is one reason why a quality control mechanism is required to assure
accurate chromosome segregation.
The quality control process is called the SAC. The major SAC proteins
(Mad1, Mad2, Mps1, Bub1, BubR1) associate with unattached kineto-
chores in prometaphase. The SAC apparatus surveys the state of K-MT
attachment, and in the presence of an unattached kinetochore, the SAC gen-
erates an inhibitor of anaphase onset ( Li and Nicklas, 1995; Rieder et al.,
1995 ). This delay gives the cell more time to correct the attachment errors.
In response to the establishment of proper K-MT attachment, the SAC
apparatus is dismantled from kinetochores and the source of the anaphase
inhibitor is thus shut off. A defective SAC mechanism would allow a cell
with an improperly attached kinetochore to enter anaphase, thus generating
two aneuploid daughter cells.
Two key proteins maintain the cell in prometaphase: Cyclin B, the reg-
ulatory subunit of the master mitotic kinase Cdk1, and Securin, the inhibitor
of separase, a cohesin protease that otherwise would sever the links binding
sister chromatids together. The stability of these two proteins is regulated by