Biology Reference
In-Depth Information
binding to SAS-6 must be regulated to prevent complete degradation of SAS-6.
Indeed, it appears that phosphorylation of Fbxw5 on Ser-151 by Plk4 somehow
suppresses its ability to ubiquitinate SAS-6, preventing degradation. Thus, the low
levels of Plk4 present in interphase may be sufficient to regulate the abundance of
SAS-6 by controlling the ability of Fbxw5 to target SAS-6 for degradation.
However, as Fbxw5 depletion only partially rescues the loss of centrioles caused
by Plk4 depletion, Fbxw5 cannot be the only Plk4 target involved in centriole
assembly (Puklowski et al.
2011
). This leaves open the possibility that Plk4 may
phosphorylate other centriole assembly factors, such as SAS-4/CPAP, SAS-5/
STIL, Cep152, or even SAS-6 directly (Hatch et al.
2010
; Kitagawa et al.
2009
), to
promote centriole biogenesis.
9.3.2 Regulation of Centriole Length
After procentrioles are formed in S-phase, they elongate in a proximal to distal
direction, reaching full length in G2 or mitosis. It was originally thought that
centriole length was restricted principally by kinetic constraints, with the centriolar
structural components unable to stably form a longer structure than that already
observed in the mother centriole. However, a number of studies have now shown
that centriole length is also regulated through proteolysis (Kohlmaier et al.
2009
;
Schmidt et al.
2009
; Tang et al.
2009
; Korzeniewski et al.
2010
; Vidwans et al.
2003
). SAS-4/CPAP and CP110 localize to the distal ends of growing procentri-
oles and were first described as forming a cap under which the elongating cent-
riolar microtubules were inserted (Kleylein-Sohn et al.
2007
). They have since
been shown to have potentially opposing roles as positive and negative regulators,
respectively, of centriole length. Indeed, overexpression of SAS-4/CPAP induces
excessive centriole elongation, while it is depletion of CP110 that has a similar
consequence (Schmidt et al.
2009
; Tang et al.
2009
; Korzeniewski et al.
2010
). Not
surprisingly, then, the abundance of each protein is again carefully regulated by
cell cycle-dependent degradation.
SAS-4/CPAP is absent in G1, with levels gradually increasing from early S-
phase to mitosis. As cells exit mitosis, SAS-4/CPAP protein levels fall, concurrent
with decreased abundance of SAS-6. As SAS-4/CPAP binds to Cdh1, but not
Cdc20, and contains a functional KEN- and D-box, it is likely to be a target of
APC/C
Cdh1
. If SAS-4/CPAP levels are not controlled, for example, due to over-
expression of wild-type or a non-degradable mutant, extended microtubule fila-
ments are generated with properties that are highly reminiscent of elongated
centriolar structures. In fact, both parental centrioles and procentrioles undergo
elongation in the presence of excess SAS-4/CPAP, with no increase in overall
centriole numbers (Schmidt et al.
2009
). SAS-4/CPAP contains both tubulin
dimer- and microtubule-binding domains, along with an ability to destabilize
microtubules (Cormier et al.
2009
; Hsu et al.
2008
), suggesting that SAS-4/CPAP
is able to regulate the assembly of centriolar microtubules. Indeed, mutation of the
