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Biochemical Society Transactions (2010) Volume 38, part 5
Systems-level feedback in cell-cycle control
Béla Novák1 , P.K. Vinod, Paula Freire and Orsolya Kapuy
Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
Abstract
Alternation of chromosome replication and segregation is essential for successful completion of the cell
cycle and it requires an oscillation of Cdk1 (cyclin-dependent kinase 1)–CycB (cyclin B) activity. In the
present review, we illustrate the essential features of checkpoint controlled and uncontrolled cell-cycle
oscillations by using mechanical metaphors. Despite variations in the molecular details of the oscillatory
mechanism, the underlying network motifs responsible for the oscillations are always well-conserved.
The checkpoint-controlled cell cycles are always driven by a negative-feedback loop amplified by
double-negative feedbacks (antagonism).
Alternation of chromosome replication
and segregation
During the cell division cycle, cells must replicate their
DNA first and segregate the end-products of the replication
process (sister chromatids) later. In order to preserve the
genetic information encoded by chromosomes, these two
processes, chromosome replication and segregation, must
alternate with each other during the cell cycle [1]. This strict
alternation of chromosome replication and segregation is
ensured by biochemical regulatory mechanisms (Figure 1).
Eukaryotic chromosome replication is triggered by Cdk
(cyclin-dependent kinase) activity. Cdks are active in complex
with their cyclin partners [2] and in lower eukaryotes Cdk1–
CycB (cyclin B) dimers initiate S-phase. In order to avoid
over-replication of the genome, a licensing control system
ensures that each replication origin is activated only once per
cell cycle [3]. Origin firing and licensing are co-ordinated
via Cdk activity, which besides activating origin firing, also
inactivates components in the licensing system [4]. Therefore
replication origins are licensed in a low Cdk activity (G1 )
phase of the cell cycle (Figure 1).
DNA replication produces two identical sister chromatids
which are held together by cohesin complexes [5]. The rule of
strict alternation requires that DNA replication is followed
by chromosome segregation (anaphase) which depends on
removal of cohesins from chromosomes. Cohesins are cleaved
by a specific protease, separase, when the inhibitor of
separase, securin, is degraded [6]. Chromosome segregation
(anaphase) is initiated by activation of APC/C (anaphasepromoting complex [7]/cyclosome [8]) ubiquitin-ligase
which targets securin for proteasome-dependent degradation,
thereby activating separase. The other essential substrate of
APC/C is the CycB subunit of the Cdk1–CycB complex. The
Key words: bistability, cell cycle, feedback, oscillation.
Abbreviations used: APC/C, anaphase-promoting complex/cyclosome; Cdh1, cadherin 1; Cdk,
cyclin-dependent kinase; CKI, Cdk inhibitor; CycB, cyclin B; SK, starter kinase.
1
To whom correspondence should be addressed (email [email protected]).
C The
C 2010 Biochemical Society
Authors Journal compilation concomitant degradation of CycB during anaphase inactivates Cdk and thereby allows replication origins to re-license.
In summary, the alternation of DNA replication and
chromosome segregation requires a fluctuation in Cdk
activity between low and high values. The oscillation in
Cdk activity is provided by systems-level feedback loops.
The simplest Cdk oscillator is operating in early embryos
(such as Xenopus and Drosophila) and it is based on the
negative-feedback loop between Cdk and APC/C [9]. In the
following discussion we present simple mechanical models to
illustrate the main features of eukaryotic cell-cycle controls
and we direct interested readers to the original publications
for the corresponding mathematical models [10–19].
The Cdk–APC/C negative-feedback loop
A good illustration of the Cdk–APC/C negative-feedback
loop is the Japanese deer chaser Shishi Odoshi (Figure 2).
The open end of the hollow arm corresponds to Cdk activity,
which is lifted up by the heavy closed end of the arm (CycB
synthesis) and the rising water level in the hollow arm
corresponds to APC/C activation. The arm tips over once
the weight of the water exceeds a threshold determined by
the weight at the closed end. At this point the water flows
out, the arm is emptied and it rises again. The arm oscillates
between low and high values similar to Cdk activity during
the cell cycle. Observe that APC/C activity (water in the
arm) oscillates as well: when the arm is in the upper position
(high Cdk) APC/C activity increases, whereas APC/C
decreases when the arm is in the lower position (low Cdk).
The rising and falling water levels in the arm introduce
important time-delays which are essential for oscillators
based on negative-feedback only [20].
This Cdk–APC/C negative-feedback oscillator operates
in such an ‘uncontrolled’ way only in some early embryos
such as Xenopus [21]. In non-embryonic cells the oscillator
is controlled by checkpoint mechanisms that stop the
oscillator in low (before DNA replication) and high (before
chromosome segregation) Cdk activity states.
Biochem. Soc. Trans. (2010) 38, 1242–1246; doi:10.1042/BST0381242
Signalling and Control from a Systems Perspective
Figure 1 Strict alternation of chromosome replication and
segregation driven by the Cdk–APC/C negative-feedback loop
The Cdk–CycB complex triggers replication and activates APC/C
and blocks re-licensing. In contrast, APC/C promotes chromosome
segregation, cyclin destruction and re-licensing. Lines represent DNA
double helices, and large and small blobs indicate protein complexes of
replication origin and licensing system respectively.
Figure 2 The Japanese garden device, Shishi Odoshi, operates
like the eukaryotic embryonic cell-cycle clock
(A) Dripping water fills up the hollow pivoting arm of the device.
(B) When the arm is full (APC/C activated) the weight of the water
causes the arm to tip over (cyclin degradation) and empty (APC/C
inactivation). The empty arm is then free to swing back up into position
and refill.
relationship with Cdk activity [13]. As a consequence
APCCdh1 can be represented as a heavy ball (see Figure 3) in
our mechanical metaphor [24]. When the ball is rolled out,
APCCdh1 is active and Cdk activity is kept low (arm down).
On the other hand, when Cdk activity is high (arm is up) the
ball is back to the hinge and APCCdh1 is inactive.
In fact, the G1 checkpoint also uses a stoichiometric CKI
(Cdk inhibitor; called Sic1 and Rum1 in budding and fission
yeasts respectively) to keep Cdk activity low in G1 phase
[25,26]. The CKI also behaves like a ball in the mechanism
because its relationship with Cdk activity is also antagonistic:
the Cdk1–CycB complex inhibits the transcription [27,28]
and promotes the degradation of its inhibitor (CKI) in yeast
[29,30].
In order to terminate the G1 checkpoint, cells require SK
(starter kinase) molecules that inactivate APCCdh1 and the
CKI [31]. Usually cells use Cdk–cyclin complexes (such as
Cdk1–Cln complexes in budding yeast) as SKs which are
resistant to inhibition by APCCdh1 and the CKI. SKs can be
represented as a force that pushes back the ball to the hinge
where its exerted torque is zero (Figure 3C). Inactivation
of APCCdh1 and the CKI by SKs allow CycB synthesis to
raise Cdk activity and to initiate S- and M-phases. Once
the ball is pushed back to the upright support and Cdk
activity is self-maintaining, the SK has to be inactivated. This
is important for subsequent cell-cycle transition, because
permanent activation of the SK could inhibit the rolling out
of the ball at the time of APCCdc20 activation [31]. For this
reason Cdk1–CycB activity represses the transcription of
cyclin components of the SK [32].
Once the G1 checkpoint is in place, the chromosome cycle
is dictated by the timing of SK activation rather than by the
free-running cell-cycle clock [13]. Since this is often linked
to reaching a critical cell size [33], the G1 checkpoint allows
co-ordination of the chromosome cycle with cytoplasmic
growth.
The mitotic checkpoint
The G1 checkpoint
The G1 checkpoint blocks the cell-cycle clock in the low
Cdk activity (G=) state by keeping APC/C active which
promotes CycB degradation. Since the form of APC/C
(called APCCdc20 ) promoting chromosome segregation is
inactivated at low Cdk activity, the G1 checkpoint uses
another form of APC/C (called APCCdh1 ). APCCdh1 is active
at low Cdk activity, but it is inactivated by Cdk-dependent
phosphorylation [22,23]. Since APCCdh1 promotes CycB
degradation by ubiquitination, it has an antagonistic
The high Cdk activity state is stabilized by the mitotic
checkpoint that blocks APCCdc20 activation (water flow)
until all of the chromosomes have a bipolar attachment to
the spindle [34]. Once the mitotic checkpoint is lifted, the
activation of APCCdc20 (water in the hollow arm) promotes
complete destruction of CycB and thereby drives mitotic exit.
The drop in Cdk activity caused by APCCdc20 can activate
APCCdh1 and CKI (rolling out of the ball) with passive help
from a phosphatase. Interestingly, in budding yeast APCCdc20
can trigger anaphase by activating separase via complete
degradation of securin, but it fails to destroy all of the CycB
and, therefore, it does not allow rolling out of the ball as well.
Therefore mitotic exit in budding yeast requires an active role
from the Cdc14 phosphatase which corresponds to a force
that pushes the ball to the right on Figure 3(B) [35]. Cdc14
phosphatase activates APCCdh1 directly and CKI indirectly
(through activation of its transcription factor, Swi5), by
dephosphorylation of their Cdk phosphorylation sites [35].
C The
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Authors Journal compilation 1243
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Biochemical Society Transactions (2010) Volume 38, part 5
Figure 3 A modified Shishi Odoshi explains the cell-cycle regulation in budding yeast
The heavy ball representing APCCdh1 and CKI (Sic1) is pushed back and forth by SKs and Cdc14 phosphatase. (A) Metaphase,
before APCCdc20 activation. (B) Anaphase, APCCdc20 activated. (C) G1 -phase, after mitotic exit. See the text for more details.
Since the Cdc14 phosphatase represents a force pushing
the ball to the right, it becomes inhibitory at the time of G1
checkpoint inactivation, when the ball needs to be pushed to
the left. Therefore Cdc14 has to be inactivated after exit from
mitosis, which is achieved by a negative-feedback loop. The
release of Cdc14 from the nucleolus is a separase-dependent
process which also requires both Cdk1–CycB [36] and
Polo-kinase [37] activities. Since Cdc14 activates APCCdh1
which promotes the degradation of both CycB [38] and
Polo-kinase [39,40], which in turn, are both required for
Cdc14 to be released, the phosphatase gets re-sequestered in
the nucleolus [41,42].
Bistable switch in the budding yeast
cell cycle
During the budding yeast cell cycle, both activation and
inactivation of Cdk are initiated by helper molecules (SKs
and Cdc14 phosphatase) which push the ball back and forth
along the arm on Figure 3. As a consequence the budding
yeast cell cycle has lost all the clock-like characteristics of
the Cdk-APCCdc20 negative-feedback loop. The budding
yeast cell-cycle control rather centres around the bistable
switch based on the antagonism between Cdk1–CycB and
its negative regulators (APCCdh1 and CKI) [13,18,43]. This
antagonism creates two alternative steady states (see Figure 3)
and the transitions between these two states are triggered by
helper molecules (SK and Cdc14) which are down-regulated
after the transition they are enforcing.
C The
C 2010 Biochemical Society
Authors Journal compilation The bistable switch in budding yeast cell-cycle control
is supported by a lot of experimental evidence. Cdc20deprived budding yeast cells are blocked with high Cdk1–
CycB activity and inactive APCCdh1 and CKI [38]. Notice
that this situation corresponds to the absence of water flow in
the Shishi Odoshi model. This high Cdk activity steady-state
is stable against ectopic (e.g. Gal promoter induced) overexpression of Cdh1 (cadherin 1) or CKI [44,45]. These Cdk1–
CycB complex inhibitors cannot work at high Cdk, because
high Cdk activity promotes the inactivation and degradation
of its negative regulators. Ectopic expression of these CKIs
represents a heavier ball in the Shishi Odoshi, which cannot
roll down because the arm is completely pulled up.
On the other hand, ectopic expression of non-phosphorylable Cdh1 and CKI (ball components) can bypass
all Cdk controls, and destabilize the high Cdk activity
state and induce mitotic exit [44,45]. Non-phosphorylable
Cdh1 (Cdh1 constitutively active, Cdh1CA ) and CKI
(non-degradable CKI, CKInd ) are resistant to Cdk inhibition
and should be considered as forces which push down the
arm of Shishi Odoshi by down-regulating Cdk activity. As
a consequence, the ectopic expression of either of these Cdk
inhibitory molecules forces the ball (endogenous Cdh1 and
CKI) to roll out which further inhibits Cdk activity. The
mitotic exit transition becomes irreversible once the rolling
out ball stabilizes the low Cdk activity G1 state even in
the absence of the initial stimulus (Cdh1CA or CKInd ). For
instance, it has been shown recently, that Cdh1CA -induced
mitotic exit becomes irreversible after 50 min [44].
Signalling and Control from a Systems Perspective
controlled cell cycles are driven by a negative-feedback loop
amplified by double-negative feedback (antagonism).
Mitotic exit induced by non-phosphorylable Cdk
inhibitors (Cdh1 or CKI) takes place in the absence of
anaphase because separase is not activated in the absence
of Cdc20-dependent securin degradation. Since Cdc14
activation is separase-dependent, Cdc14 release from the
nucleolus is compromised and the activation of endogenous
Cdh1 and CKI is slow, i.e. the ball rolls out slowly. The
mitotic exit process can be accelerated by overexpression of
Cdc14 phosphatase [44] or inducing anaphase [45].
Acknowledgements
Cycling without APC/C
Funding
The cells forced to exit from mitosis in the absence of
Cdc20 are inviable because APCCdc20 is essential for
securin degradation and thereby for anaphase. This Cdc20
requirement of anaphase can be easily bypassed by securin
(called Pds1 in budding yeast) deletion and cdc20pds1
double mutants undergo normal anaphase [46,47]. Although
Cdc14 phosphatase is activated [47], it is not strong enough to
overcome the high Cdk activity (Cdc14 cannot push the ball
out from the hinge). This block of mitotic exit can be overcome by either reduction of Cdk activity or overexpression
of CKI (called Sic1 in budding yeast). The Cdk activity can
be reduced by deleting one of the early-acting cyclin genes
such as Clb5, and cdc20pds1clb5 triple-mutant cells can
exit from mitosis [47]. Overexpression of the stoichiometric
CKI makes the ball heavier which, with the help of
Cdc14, can down-regulate Cdk activity as well [48]. The
combination of these two effects (reduced cyclin level and
CKI overexpression) in the cdc20cdh1pds1clb5sic1op
mutant makes APC/C altogether dispensable for budding
yeast cells [48]. The viability of this quintuple mutant shows
that alternation of chromosome replication and segregation
only requires oscillation in Cdk activity, but not APC/C.
In the absence of APC/C-dependent cyclin degradation, the
Cdk1–CycB activity oscillations are driven by fluctuating
CKI levels at more or less constant CycB levels. At high
Cdk1–CycB activity, Sic1 gets up-regulated through Cdc14dependent activation of its transcription factor, Swi5 and
inhibits Cdk1–CycB complexes. However down-regulation
of Cdk1–CycB activities up-regulates SK (Cdk1–Clns) which
are not inhibited by Sic1 and they promote Sic1 degradation.
The oscillating Cdk1–CycB activity co-ordinates DNA
replication with anaphase as well, because cohesin cleavage
is regulated not only by separase, but also at the substrate
(cohesion) level. Cohesin cleavage is dependent on prior
phosphorylation of cohesin by Polo-kinase [49], the activity
of which is dependent on Cdk1–CycB [50].
This work was supported by the Biotechnology and Biological
Sciences Research Council (OCISB grant); and Unicellsys [European
Commission Framework Programme 7 number 201142].
Conclusions
The oscillation of Cdk1–CycB activity required for the
successful completion of the cell cycle can be achieved by
different biochemical mechanisms. Although the molecular
details could be different, the underlying network motifs
are well-conserved. The Cdk oscillation in checkpoint-
We are grateful to Hisao Moriya (Okayama University, Okayama,
Japan) for pointing out that the mechanical device in our publication
[24] is called Shishi Odoshi in Japan.
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Received 8 March 2010
doi:10.1042/BST0381242