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the DDR, mediated in part by BubR1. In Drosophila , it has been shown, for
example, that BubR1 and the DNA damage checkpoint kinase Chk1 (prod-
uct of the grp gene) are involved in delaying metaphase-anaphase transition
after extensive radiation-induced DNA damage in larval neuroblasts ( Royou
et al., 2005 ).
Supporting evidence that BubR1 is involved in the DDR also comes
from mammalian cells. Fang et al. (2006) showed that BubR1 þ / mouse
embryo fibroblasts (MEFs) displayed a weakened physiological response to
genotoxic stress caused either by treatment with UV or the DNA topo-
isomerase 2 inhibitor doxorubicin (which induces double-strand breaks).
The treated cells failed to arrest at G2/M and moreover displayed lower
levels of phospho-H2AX and tumor suppressor p53, both of which nor-
mally increase in response to DNA damage. Fang et al. also reported that
BubR1 coimmunoprecipitated with the poly(ADP-ribose) polymerase
I (PARP-1), an enzyme implicated in the activation of p53 in response
to DNA damage ( Huberetal.,2004 ), and moreover that PARP-1 was less
stable in BubR1 þ / MEFs. Interestingly, BubR1 was also reported to
phosphorylate and stabilize p53 in response to spindle damage
( Ha et al., 2007 ).
Finally, we note that PARP-1 and poly(ADP)ribose modifications have
been detected at kinetochores ( Saxena et al., 2002 ) and also are reportedly
required for proper assembly and the maintenance of bipolar spindles
( Chang et al., 2004 ). It is possible therefore that the link between
PARP-1 and BubR1 may have implications for spindle assembly as well.
Damaged telomeres are known to elicit a DDR ( de Lange, 2005; Lydall,
2003 ). In Drosophila larval neuroblasts, uncapped telomeres were shown to
activate both the DDR and the SAC, arresting cells at either interphase or
M-phase ( Musaro et al., 2008 ). A possible role for BubR1 in signaling telo-
mere damage was reported in this study. The M-phase arrest could be par-
tially suppressed by mutations in SAC components including BubR1,
indicating that the observed delay is due to the activation of the SAC.
However, in addition to being localized at kinetochores as are the other
components of the SAC, BubR1 was also found on the uncapped telomeres.
Moreover, BubR1's recruitment to telomeres was dependent on compo-
nents of the DDR pathway including mei41/ATR, mus304/ATRIP,
grp/Chk1, and tefu/ATM. The authors suggested that the local activation
of the SAC at damaged telomeres may serve as a backup mechanism to pre-
vent genomic instability that could be generated by damaged chromosome
ends ( Musaro et al., 2008 ).
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