New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 252

BubR1 and Mad2 have also been reported to localize at the telomeres of
mouse epithelial cells that overexpress TRF1 (telomeric-repeat-binding fac-
tor 1), a component of the Shelterin protein complex that specifically binds
chromosome ends ( Munoz et al., 2009 ). Whether this leads to the activation
of the SAC was not addressed. Nevertheless, these findings indicate that dys-
functional telomeres may elicit not only a DDR but also an activation of the
SAC that would be mediated (at least in part) by BubR1.
Another unexpected intervention of BubR1 in response to DNA dam-
age was described in Drosophila by Royou et al. (2010) . They reported that a
BubR1-dependent mechanism helped assure the correct mitotic segregation
of nominally acentric chromosome fragments. In their system, acentric frag-
ments of the X and Y chromosomes were generated by pulsed expression of
the I-CreI endonuclease ( Rong et al., 2002 ). These acentric fragments
became linked to their centromere-containing partners by DNA tethers
decorated with BubR1 (as well as Polo, INCENP, and Aurora B, but
not KMN components). In cells expressing bubR1 or polo hypomorphic
mutant alleles, a large fraction of the acentric chromatids remained
untethered, resulting in a high percentage of aneuploid cells and lethality
( Royou et al., 2010 ). While the nature of the tethers and the mechanism
by which they form are still not known, the authors suggest that BubR1
may somehow stabilize the repair machinery that holds the chromosome
fragments together.
5.3. Centrosomes and cilia
Several reports suggest that BubR1 may play a role in regulating centrosome
amplification. Mutations or loss of p53 in mammalian cells is known to lead
to centrosome amplification. Oikawa et al. (2005) reported that in these cells
the reduced expression of BubR1 (whose transcription is positively regu-
lated by P53) is a major contributor to the centrosome amplification pheno-
type. Furthermore, some cells derived from patients with BubR1 mutations
(MVA syndrome, see below) displayed centrosome amplification and mul-
tipolar mitosis ( Izumi et al., 2009 ). BubR1 was shown to localize to centro-
somes during interphase in several cell types via the middle domain of the
protein (between residues 240 and 639) ( Izumi et al., 2009 ). This
centrosomal localization was dependent on Plk1, and indeed BubR1
directly interacted with the Polo-box domain of Plk1 in vitro , negatively reg-
ulating Plk1 activity. Overexpression of Plk1 in HeLa cells induced centro-
some amplification and multipolar mitosis in 40% of transfected cells.