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In-Depth Information
Plk4-dependent centriole overproduction (Korzeniewski et al.
2009
), and Plk4 is
regulated by the Slimb/bTrCP F-box protein in both flies (Rogers et al.
2009
;
Cunha-Ferreira et al.
2009
) and humans (Guderian et al.
2010
) [reviewed in
(Sillibourne and Bornens
2010
)]. SCF-dependent degradation is typically stimu-
lated by substrate phosphorylation, and in the case of Plk4 it is an autophospho-
rylation event that promotes Slimb/bTrCP binding (Guderian et al.
2010
).
Accordingly, autoactivation of Plk4 ensures its own destruction, limiting the levels
of active Plk4 as part of the regulation of the initiation of centriole assembly.
SCF has additionally been shown to control centrosome homeostasis through
the cyclin F-dependent degradation of CP110. Despite being the protein for which
the F-box was named, cyclin F remained an orphan protein until MudPIT analysis
showed that it bound to Skp1 and Cul1 in an F-box independent manner, and to
CP110 in an F-box dependent manner (D'Angiolella et al.
2010
). Interestingly, the
binding of CP110 to the F-box in cyclin F is not regulated by phosphorylation as is
typical for other SCF ligases, but rather by an RxL cyclin-binding motif in CP110.
Regardless, either the depletion of cyclin F or the expression of a CP110 mutant
that fails to bind cyclin F leads to centrosome overproduction, punctuating the
importance of SCF function in controlling centrosome homeostasis (D'Angiolella
et al.
2010
).
8.9 BRCA1 and the Centrosome
The BRCA1 breast cancer susceptibility gene encodes a RING domain protein that
has E3 ligase activity when bound to its partner BARD1 [reviewed in (Parvin
2009
; Deng
2006
)]. In 1998 BRCA1 was seen to associate with mitotic centro-
somes (Hsu and White
1998
), and in 1999 it was shown that mice with a targeted
deletion of BRCA1 exon 11 undergo centrosome amplification (Xu et al.
1999
).
It was later shown that BRCA1 binds to c-Tubulin to regulate its recruitment to
centrosomes (Hsu et al.
2001
). BRCA1 binds to c-Tubulin, and overexpression of
the BRCA1 c-Tubulin binding domain displaces endogenous BRCA1 from cen-
trosomes and dominantly interferes with the centrosomal recruitment of c-Tubulin
(Hsu et al.
2001
). Only hypophosphorylated BRCA1 was capable of binding to
c-Tubulin (Hsu et al.
2001
), and it was subsequently shown that Aurora A phos-
phorylates BRCA1 and inhibits its centrosomal functions (Ouchi et al.
2004
;
Sankaran et al.
2007
). In a search for relevant centrosomal targets of BRCA1 E3
ligase activity, BRCA1 was found to monoubiquitylate c-Tubulin in vitro at lysine
48 (Starita et al.
2004
). The ubiquitylation of c-Tubulin by BRCA1 requires the
BRCA1 RING domain (Starita et al.
2004
) and its E3 ligase activity (Sankaran
et al.
2006
), as well as its partner BARD1 that is localized to centrosomes
throughout the cell cycle (Sankaran et al.
2006
). While BRCA1 appeared to
ubiquitylate other proteins in isolated centrosomes, c-Tubulin would appear to be
largely responsible for the centrosomal functions of BRCA1, because expression
of a K48R mutant c-Tubulin that could not be ubiquitylated caused a dominant
