Biology Reference
In-Depth Information
BRCA1, breast cancer-associated gene 1, a major DNA repair factor, is also
known to be involved in the regulation of centrosome number. BRCA1 localizes to
the centrosome and its depletion results in the formation of extra centrosomes, a
phenotype that is specific to mammary epithelial cells suggesting the dependency
of mammary cells on the activity of BRCA1 in the prevention of centrosome
overduplication (Ko et al.
2006
; Starita et al.
2004
). The regulation of the cen-
trosome by BRCA1 will be discussed further in the following section. BRCA2,
breast cancer-associated gene 2, is another key player in HR that is known to
control centrosome number. BRCA2 localizes to the centrosome and its depletion
results in centrosome overduplication strengthening the relationship between a
defect in DNA repair and abnormal centrosome numbers (Nakanishi et al.
2007
).
Another DNA repair factor that localizes to the centrosome is NBS1. At the
centrosome, NBS1 regulates the BRCA1-mediated ubiquitination of gamma-
tubulin through its interaction with ATR. Similar to the phenotype caused by
BRCA1 and ATR depletion, NBS1 depletion leads to centrosome amplification
(Shimada et al.
2009
). RAD51 is another HR repair factor whose depletion results
in centrosomal abnormalities (Bertrand et al.
2003
). Centrosome reduplication
upon RAD51 depletion occurs in a prolonged G2 arrest due to the activation of the
G2-M checkpoint in response to DNA damage that accumulates as a consequence
of a defective DNA repair system. Thus, a defect in the DNA repair machinery
will arrest cells in G2 due to the activation of a G2-M checkpoint and this would
eventually cause centrosome amplification.
14.3 BRCA1 and the Centrosome
BRCA1 is a multifunctional protein involved in several cellular processes
including DNA repair, cell cycle checkpoints, transcription control, and mainte-
nance of the centrosome (Sankaran et al.
2006
; Venkitaraman
2002
). BRCA1
heterodimerizes with BARD1 to form a complex with an E3 ubiquitin ligase
activity that catalyzes the transfer of ubiquitin moiety to a target protein. Similar to
other E3 ubiquitin ligases, BRCA1/BARD1 can either monoubiquitinate or
polyubiquitinate targeted proteins. Polyubiquitination on lysine 48 will target the
protein for proteasomal degradation. Monoubiquitination of a protein also has
several effects including intracellular trafficking or simply blocking the modifi-
cation of an important lysine. Inhibition of BRCA1 by expressing a protein
fragment that binds to its carboxy terminus or by RNA interference (RNAi) results
in supernumerary centrosomes in mammary epithelial cells (Starita et al.
2004
).
BRCA1 and BARD1 both localize to the centrosome at all stages of the cell cycle
(Hsu and White
1998
; Sankaran et al.
2006
) and the ubiquitin ligase activity of the
protein regulates both centrosome number and function (Kais and Parvin
2008
).
Starita et al.
2004
found that the BRCA1/BARD1 complex ubiquitinates gamma-
tubulin,
a
major
centrosomal
protein,
at
gamma-tubulin
residue
lysine 48.
Expression
of
a
mutant
form
of
gamma-tubulin
with
a
lysine
to
arginine
