G2 phase

G2 phase, Gap 2 phase, or Growth 2

phase, is the third subphase of
interphase in the cell cycle directly
preceding mitosis. It follows the
successful completion of S phase, during
which the cell’s DNA is replicated. G2
phase ends with the onset of prophase,
the first phase of mitosis in which the
cell’s chromatin condenses into
chromosomes.
Mitosis in an animal cell (phases ordered counter-
clockwise), with G2 labeled at bottom.

Schematic karyogram of the human

chromosomes, showing their usual state in
the G0 and G1 phase of the cell cycle. At
top center it also shows the chromosome 3
pair after having undergone DNA synthesis,
occurring in the S phase (annotated as S)
of the cell cycle. This interval includes the
G2 phase and metaphase (annotated as
"Meta.").
G2 phase is a period of rapid cell growth
and protein synthesis during which the
cell prepares itself for mitosis. Curiously,
G2 phase is not a necessary part of the
cell cycle, as some cell types (particularly
young Xenopus embryos[1] and some
cancers[2]) proceed directly from DNA
replication to mitosis. Though much is
known about the genetic network which
regulates G2 phase and subsequent
entry into mitosis, there is still much to
be discovered concerning its significance
and regulation, particularly in regards to
cancer. One hypothesis is that the growth
in G2 phase is regulated as a method of
cell size control. Fission yeast
(Schizosaccharomyces pombe) has been
previously shown to employ such a
mechanism, via Cdr2-mediated spatial
regulation of Wee1 activity.[3] Though
Wee1 is a fairly conserved negative
regulator of mitotic entry, no general
mechanism of cell size control in G2 has
yet been elucidated.

Biochemically, the end of G2 phase

occurs when a threshold level of active
cyclin B1/CDK1 complex, also known as
Maturation promoting factor (MPF) has
been reached.[4] The activity of this
complex is tightly regulated during G2. In
particular, the G2 checkpoint arrests cells
in G2 in response to DNA damage
through inhibitory regulation of CDK1.
Homologous
recombinational repair
During mitotic S phase, DNA replication
produces two nearly identical sister
chromatids. DNA double-strand breaks
that arise after replication has
progressed or during the G2 phase can
be repaired before cell division occurs
(M-phase of the cell cycle). Thus, during
the G2 phase, double-strand breaks in
one sister chromatid may be repaired by
homologous recombinational repair
using the other intact sister chromatid as
template.[5]

End of G2/entry into mitosis

Mitotic entry is determined by a
threshold level of active cyclin-B1/CDK1
complex, also known as cyclin-B1/Cdc2
or the maturation promoting factor
(MPF). Active cyclin-B1/CDK1 triggers
irreversible actions in early mitosis,
including centrosome separation, nuclear
envelope breakdown, and spindle
assembly. In vertebrates, there are five
cyclin B isoforms (B1, B2, B3, B4, and
B5), but the specific role of each of these
isoforms in regulating mitotic entry is still
unclear. It is known that cyclin B1 can
compensate for loss of both cyclin B2
(and vice versa in Drosophila).[6]
Saccharomyces cerevisiae contains six B-
type cyclins (Clb1-6), with Clb2 being the
most essential for function. In both
vertebrates and S. cerevisiae, it is
speculated that the presence of multiple
B-type cyclins allows different cyclins to
regulate different portions of the G2/M
transition while also making the
transition robust to perturbations.[7]

Subsequent discussions will focus on the

spatial and temporal activation of cyclin
B1/CDK in mammalian cells, but similar
pathways are applicable in both other
metazoans and in S. cerevisiae.

Cyclin B1 synthesis and degradation

Cyclin B1 levels are suppressed
throughout G1 and S phases by the
anaphase-promoting complex (APC), an
E3 ubiquitin ligase which targets cyclin
B1 for proteolysis. Transcription begins
at the end of S phase after DNA
replication, in response to
phosphorylation of transcription factors
such as NF-Y, FoxM1 and B-Myb by
upstream G1 and G1/S cyclin-CDK
complexes.[8]

Regulation of cyclin-B1/CDK1
activity

Increased levels of cyclin B1 cause rising

levels of cyclin B1-CDK1 complexes
throughout G2, but the complex remains
inactive prior to the G2/M transition due
to inhibitory phosphorylation by the Wee1
and Myt1 kinases. Wee1is localized
primarily to the nucleus and acts on the
Tyr15 site, while Myt1 is localized to the
outer surface of the ER and acts
predominantly on the Thr14 site.

The effects of Wee1 and Myt1 are

counteracted by phosphatases in the
cdc25 family, which remove the inhibitory
phosphates on CDK1 and thus convert
the cyclin B1-CDK1 complex to its fully
activated form, MPF.
 This diagram illustrates the feedback
loops underlying the G2/M transition.
Cyclin-B1/CDK1 activates Plk and
inactivates Wee1 and Myt1. Activated
Plk activates cdc25. Activation of
Cdc25 and inactivation of Wee1/Myt1
lead to further activation of Cyclin-
B1/CDK1. Also shown is the putative
role of cyclin-A/CDK2 and Cdc25A as
initial activators of the feedback loop,
discussed in a later section.

Active cyclinB1-CDK1 phosphorylates

and modulates the activity of Wee1 and
the Cdc25 isoforms A and C. Specifically,
CDK1 phosphorylation inhibits Wee1
kinase activity, activates Cdc25C
phosphatase activity via activating the
intermediate kinase PLK1, and stabilizes
Cdc25A. Thus, CDK1 forms a positive
feedback loop with Cdc25 and a double
negative feedback loop with Wee1
(essentially a net positive feedback
loop).

Positive feedback and switch-like

activation

This graph illustrates the stable

equilibria for cyclin-B1/CDK1 activity
at varying cyclin B1 concentrations,
with the threshold of cyclin B
concentration for entering mitosis
higher than the threshold for exiting
mitosis.

These positive feedback loops encode a

hysteretic bistable switch in CDK1
activity relative to cyclin B1 levels (see
figure). This switch is characterized by
two distinct stable equilibria over a
bistable region of cyclin B1
concentrations. One equilibrium
corresponds to interphase and is
characterized by inactivity of Cyclin-
B1/CDK1 and Cdc25, and a high level of
Wee1 and Myt1 activity. The other
equilibrium corresponds to M-phase and
is characterized by high activity of Cyclin-
B1/CDK1 and Cdc25, and low Wee1 and
Myt1 activity. Within the range of
bistability, a cell’s state depends upon
whether it was previously in interphase or
M-phase: the threshold concentration for
entering M-phase is higher than the
minimum concentration that will sustain
M-phase activity once a cell has already
exited interphase.

Scientists have both theoretically and

empirically validated the bistable nature
of the G2/M transition. The Novak-Tyson
model shows that the differential
equations modelling the cyclin-B/CDK1-
cdc25-Wee1-Myt1 feedback loop admit
two stable equilibria over a range of
cyclin-B concentrations.[9] Experimentally,
bistability has been validated by blocking
endogenous cyclin B1 synthesis and
titrating interphase and M-phase cells
with varying concentrations of non-
degradable cyclin B1. These experiments
show that the threshold concentration for
entering M-phase is higher than the
threshold for exiting M-phase: nuclear
envelope break-down occurs between
32-40 nm cyclin-B1 for cells exiting
interphase, while the nucleus remains
disintegrated at concentrations above
16-24 nm in cells already in M-phase.[10]

This bistable, hysteretic switch is

physiologically necessary for at least
three reasons.[11] First, the G2/M
transition signals the initiation of several
events, such as chromosome
condensation and nuclear envelope
breakdown, that markedly change the
morphology of the cell and are only
viable in dividing cells. It is therefore
essential that cyclin-B1/CDK1 activation
occurs in a switch-like manner; that is,
cells should rapidly settle into a discrete
M-phase state after the transition, and
should not persist in a continuum of
intermediate states (e.g., with a partially
decomposed nuclear envelope). This
requirement is satisfied by the sharp
discontinuity separating the interphase
and M-phase equilibrium levels of CDK1
activity; as the cyclin-B concentration
increases beyond the activation
threshold, the cell rapidly switches to the
M-phase equilibrium.

Secondly, it is also vital that the G2/M

transition occur unidirectionally, or only
once per cell cycle Biological systems
are inherently noisy, and small
fluctuations in cyclin B1 concentrations
near the threshold for the G2/M
transition should not cause the cell to
switch back and forth between
interphase and M-phase states. This is
ensured by the bistable nature of the
switch: after the cell transitions to the M-
phase state, small decreases in the
concentration of cyclin B do not cause
the cell to switch back to interphase.

Finally, the continuation of the cell cycle

requires persisting oscillations in cyclin-
B/CDK1 activity as the cell and its
descendants transition in and out of M-
phase. Negative feedback provides one
essential element of this long-term
oscillation: cyclin-B/CDK activates
APC/C, which causes degradation of
cyclin-B from metaphase onwards,
restoring CDK1 to its inactive state.
However, simple negative feedback loops
lead to damped oscillations that
eventually settle on a steady state.
Kinetic models show that negative
feedback loops coupled with bistable
positive feedback motifs can lead to
persistent, non-damped oscillations (see
relaxation oscillator) of the kind required
for long-term cell cycling.

Positive feedback
The positive feedback loop mentioned
above, in which cyclin-B1/CDK1
promotes its own activation by inhibiting
Wee1 and Myst1 and activating cdc25,
does not inherently include a “trigger”
mechanism to initiate the feedback loop.
Recently, evidence has emerged
suggesting a more important role for
cyclin A2/CDK complexes in regulating
the initiation of this switch. Cyclin
A2/CDK2 activity begins in early S phase
and increases during G2. Cdc25B has
been shown to dephosphorylate Tyr15 on
CDK2 in early-to-mid G2 in a manner
similar to the aforementioned CDK1
mechanism. Downregulation of cyclin A2
in U2OS cells delays cyclin-B1/CDK1
activation by increasing Wee1 activity
and lowering Plk1 and Cdc25C activity.
However, cyclin A2/CDK complexes do
not function strictly as activators of
cyclin B1/CDK1 in G2, as CDK2 has been
shown to be required for activation of the
p53-independent G2 checkpoint activity,
perhaps through a stabilizing
phosphorylation on Cdc6. CDK2-/- cells
also have aberrantly high levels of
Cdc25A. Cyclin A2/CDK1 has also been
shown to mediate proteasomal
destruction of Cdc25B. These pathways
are often deregulated in cancer.[7]

Spatial regulation
In addition to the bistable and hysteretic
aspects of cyclin B1-CDK1 activation,
regulation of subcellular protein
localization also contributes to the G2/M
transition. Inactive cyclin B1-CDK1
accumulates in the cytoplasm, begins to
be activated by cytoplasmic cdc25, and
then is rapidly sequestered into the
nucleus during prophase (as it is further
activated). In mammals, cyclin B1/CDK1
translocation to the nucleus is activated
by phosphorylation of five serine sites on
cyclin B1's cytoplasmic retention site
(CRS): S116, S26, S128, S133, and S147.
In Xenopus laevis, cyclin B1 contains four
analogous CRS serine phosphorylation
sites (S94, S96, S101, and S113)
indicating that this mechanism is highly
conserved. Nuclear export is also
inactivated by phosphorylation of cyclin
B1's nuclear export signal (NES). The
regulators of these phosphorylation sites
are still largely unknown but several
factors have been identified, including
extracellular signal-regulated kinases
(ERKs), PLK1, and CDK1 itself. Upon
reaching some threshold level of
phosphorylation, translocation of cyclin
B1/CDK1 to the nucleus is extremely
rapid. Once in the nucleus, cyclin
B1/CDK1 phosphorylates many targets in
preparation for mitosis, including histone
H1, nuclear lamins, centrosomal proteins,
and microtubule associated proteins
(MAPs).

The subcellular localization of cdc25

also shifts from the cytosol to the
nucleus during prophase. This is
accomplished via removal of nuclear
localization sequence (NLS)-obscuring
phosphates and phosphorylation of the
nuclear export signal. It is thought that
the simultaneous transport of cdc25 and
cyclin-B1/CDK1 into the nucleus amplify
the switch-like nature of the transition by
increasing the effective concentrations
of the proteins.[7]

G2/M DNA damage arrest

Cells respond to DNA damage or
incompletely replicated chromosomes in
G2 phase by delaying the G2/M transition
so as to prevent attempts to segregate
damaged chromosomes. DNA damage is
detected by the kinases ATM and ATR,
which activate Chk1, an inhibitory kinase
of Cdc25. Chk1 inhibits Cdc25 activity
both directly and by promoting its
exclusion from the nucleus.[7] The net
effect is an increase in the threshold of
cyclin B1 required to initiate the
hysteretic transition to M-phase,
effectively stalling the cell in G2 until the
damage is repaired by mechanisms such
as homology-directed repair (see
above).[4]
Long-term maintenance of the G2 arrest
is also mediated by p53, which is
stabilized in response to DNA damage.
CDK1 is directly inhibited by three
transcriptional targets of p53: p21,
Gadd45, and 14-3-3σ. Inactive Cyclin
B1/CDK1 is sequestered in the nucleus
by p21,[12] while active Cyclin B1/CDK1
complexes are sequestered in the
cytoplasm by 14-3-3σ.[13] Gadd45
disrupts the binding of Cyclin B1 and
CDK1 through direct interaction with
CDK1. P53 also directly transcriptionally
represses CDK1.[13][14]

Medical relevance
Mutations in several genes involved in
the G2/M transition are implicated in
many cancers. Overexpression of both
cyclin B and CDK1, oftentimes
downstream of loss of tumor
suppressors such as p53, can cause an
increase in cell proliferation.[7]
Experimental approaches to mitigate
these changes include both
pharmacological inhibition of CDK1 and
downregulation of cyclin B1 expression
(e.g., via siRNA).[15][16]

Other attempts to modulate the G2/M

transition for chemotherapy applications
have focused on the DNA damage
checkpoint. Pharmacologically
bypassing the G2/M checkpoint via
inhibition of Chk1 has been shown to
enhance cytotoxicity of other
chemotherapy drugs. Bypassing the
checkpoint leads to the rapid
accumulation of deleterious mutations,
which is thought to drive the cancerous
cells into apoptosis. Conversely,
attempts to prolong the G2/M arrest
have also been shown to enhance the
cytotoxicity of drugs like doxorubicin.
These approaches remain in clinical and
pre-clinical phases of research.[17]

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