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explained by a peak in expression in mitosis of the protein phosphatase 2A (PP2A)
regulatory subunit, Twins, which promotes dephosphorylation of the sites in Plk4
required for b-TrCP to bind (Brownlee et al.
2011
). Plk4 does, though, also have a
role in cytokinesis (Rosario et al.
2010
); hence, its stabilization in mitosis may
serve the purpose of cytokinesis, rather than centriole duplication. On the other
hand, overexpression of Twins promotes centriole amplification in a manner
analogous to Plk4 overexpression. This would suggest then that the activity of Plk4
in mitosis promotes centriole duplication in the ensuing S-phase.
A similar control to that described above exists in C. elegans where PP2A
promotes centriole duplication through stabilizing the levels of not only ZYG-1,
the Plk4 orthologue, but also SAS-5 (Song et al.
2011
). This raises the prospect of
course that SAS-5 levels are also controlled by phospho-dependent protein deg-
radation, although at the current time the mechanism for this is unknown. Over-
expression of the human SAS-5 orthologue, STIL, a microcephaly-related protein,
promotes centriole overduplication while depletion inhibits centriole duplication
(Tang et al.
2011
). Furthermore, depletion of STIL blocks the centriole overdu-
plication that occurs in response to Plk4 overexpression suggesting that STIL acts
downstream of Plk4, in a manner that is analogous to the model in C. elegans that
places SAS-5 downstream of ZYG-1.
Another key rate limiting step for centriole biogenesis is the expression level of
SAS-6. As for Plk4 and SAS-5, the abundance of SAS-6 directly influences the
rate of centriole formation with depletion from human cells resulting in centriole
loss over successive cell cycles and overexpression inducing centriole overdu-
plication (Leidel et al.
2005
; Strnad et al.
2007
). SAS-6 and SAS-5 play a
mutually-dependent structural role in centriole assembly, and it would appear that
strict control over the expression of both proteins is required to ensure that only
one new procentriole forms per parental centriole. In this respect, it would seem
odd that overexpression of one or the other is sufficient to drive centriole over-
duplication unless the proteins also mutually regulate the stability of each other.
The levels of SAS-6 do oscillate during the cell cycle, with the protein accumu-
lating from late G1 until it is degraded in mitosis. Consistent with this, SAS-6 is
targeted for degradation by the APC/C
Cdh1
through a KEN-box located at the C-
terminal end of the protein (Strnad et al.
2007
; Puklowski et al.
2011
). While
degradation of SAS-6 helps to limit the number of procentrioles seeded per
parental centriole to one, maintaining low SAS-6 levels in G1 may also prevent
centriole duplication commencing too early in the cell cycle (Strnad et al.
2007
).
In addition to the APC/C
Cdh1
, the SCF also targets SAS-6 for degradation via
the Fbox protein, Fbxw5. Depletion of Fbxw5 from cells causes an increase in
SAS-6 levels, centriole amplification, and multipolar spindles, while overexpres-
sion inhibits centriole formation and reduces the half-life of SAS-6 (Puklowski
et al.
2011
). Fbxw5 can bind SAS-6 and promote its ubiquitination, although a
degron in SAS-6 has yet to be identified and it is unclear whether recognition by
Fbxw5 depends on SAS-6 phosphorylation. Crucially, the levels of Fbxw5 are
regulated by the APC/C, targeting it for degradation in mitosis, before the protein
accumulates at the G1/S transition. However, with Fbxw5 present in S-phase, its
