Biology Reference
In-Depth Information
Further coupling of sister chromatid separation and centriole disengagement is
afforded by the mitotic kinase, Plk1, which also plays a role in both processes. In the
case of sister chromatids, Plk1 promotes the displacement of cohesin rings from
chromosome arms in early mitosis by phosphorylating the Scc3/SA2 subunit of
cohesin presumably leading to ring opening, while separase then cleaves the centro-
meric cohesin at the metaphase-anaphase transition (Peters et al.
2008
;Nasmyth
2011
). Regarding centriole disengagement, cells in which separase had been geneti-
cally deleted still completed disengagement, albeit with much delayed kinetics (Tsou
et al.
2009
). This delayed disengagement was absolutely dependent on Plk1. More-
over, it has now been found that arrest of cells in G2 through inhibition or depletion of
Cdk1 leads to premature centriole disengagement and that loss of either separase or
Plk1 can block this event (Loncarek et al.
2010
; Steere et al.
2011
; Prosser et al.
2012
).
The role of the APC/C in promoting centriole disengagement through triggering
degradation of securin and release of active separase is now clear. Indeed, the
premature disengagement that occurs in G2 arrest relies on the untimely activation
of the APC/C that occurs in response to Cdk1 inhibition (Prosser et al.
2012
).
Moreover, oscillation of APC/C activity during cell cycle arrest may explain the
repeated rounds of centriole disengagement and reduplication that leads to cen-
trosome amplification. Normally, during G2, the APC/C is held inactive by the
inhibitor, Emi1 (Di Fiore and Pines
2007
). However, Emi1 is itself subject to
degradation triggered by the SCF
b-TrCP
ubiquitin ligase in response to phosphor-
ylation of Emi1 by Plk1 (Hansen et al.
2004
; Moshe et al.
2004
). Thus, in the
presence of sufficient Plk1 activity, Emi1 is degraded during prolonged arrest and
the APC/C becomes active. In this sense, Plk1 acts upstream of the APC/C and
separase in centriole disengagement. However, there is growing evidence that, as
in the case of sister chromatid separation, Plk1 may also have an APC/C and
separase independent role (Prosser et al.
2012
), although whether this also involves
direct phosphorylation of cohesin proteins is an intriguing question for the future.
It has been proposed that disengagement is a prerequisite for subsequent duplication
because it frees up the site on the lateral wall of the parental centriole from which new
procentrioles grow (Tsou and Stearns
2006
). In other words, assuming that procen-
trioles emerge from a highly specific ''birth-site'' on the parental centriole and that
there is only one such site per centriole, then while it is occupied another centriole
cannot grow. While this is an elegant model, there is much to be learned about what
defines the birth-site and why, when proteins like Plk4 or SAS-6 are overexpressed,
centrioles can start growing from adjacent positions on the parental centriole.
9.5 Perspectives
As we begin to reveal the complex networks that regulate the centrosome duplication
cycle, a few general paradigms are becoming clear. First, there is intimate coupling
between the control of the DNA replication cycle and the centrosome cycle. This
''cell cycle control'' includes the use of many of the same regulatory enzymes, be
