Download A commentary on the G2/M transition of the plant cell cycle

Annals of Botany 107: 1065– 1070, 2011
doi:10.1093/aob/mcr055, available online at www.aob.oxfordjournals.org
VIEWPOINT: PART OF A SPECIAL ISSUE ON THE PLANT CELL CYCLE
A commentary on the G2/M transition of the plant cell cycle
Dennis Francis*
School of Biosciences, Cardiff University, Main Building, Cardiff CF10 3AT, UK
* E-mail [email protected]
Received: 22 December 2010 Returned for revision: 24 January 2011 Accepted: 26 January 2011
† Background The complex events of mitosis rely on precise timing and on immaculate preparation for their
success, but the G2/M transition in the plant cell cycle is currently steeped in controversy and alternative models.
† Scope In this brief review, the regulation of the G2/M transition in plants is commented on. The extent to which
the G2/M transition is phosphoregulated by WEE1 kinase and CDC25 phosphatase, as exemplified in yeasts and
animals, is discussed together with an alternative model that excludes these proteins from this transition.
Arabidopsis T-DNA insertional lines for WEE1 and CDC25 that develop normally prompted the latter model.
An argument is then presented that environmental stress is the norm for higher plants in temperate conditions.
If so, the repressive role that WEE1 has under checkpoint conditions might be part of the normal cell cycle
for many proliferative plant cells. Arabidopsis CDC25 can function as either a phosphatase or an arsenate
reductase and recent evidence suggests that cdc25 knockouts are hypersensitive to hydroxyurea, a drug that
induces the DNA-replication checkpoint. That other data show a null response of these knockouts to hydroxyurea
leads to an airing of the controversy surrounding the enigmatic plant CDC25 at the G2/M transition.
Key words: Arabidopsis thaliana, cell-cycle checkpoints, CDC25 phosphatase, cyclin-dependent kinases, G2/M,
WEE1 kinase.
IN T RO DU C T IO N
For me, one of the most exciting images in cell biology is that of a
cell in mitosis – chromosomes clustering, their aligning at the
cell plate, separating, as if on command, and re-clustering in
new nuclei. Of course, plant cells exhibit the added wonder of
a new cell wall, more often delineating a smaller and larger descendant cell. Cells get this right almost every time which for us
should be comforting and for plants in the wild, that are often
under abiotic stress, is nothing short of miraculous. It should
come as no surprise to recognize that the dangerous but successful dance of the dividing cell (see Young, 1992) relies on timing,
and relies on immaculate preparation. In this review, I will try to
focus on the preparative events of G2/M in the plant cell cycle, a
transition currently steeped in controversy and alternative
models. Of course, models are only as good as the data available
but our understanding of the G2/M transition in plants is currently mixed. My aim is to briefly review the G2/M transition
in plants. A more comprehensive account of G2/M in the
context of whole plant physiology is given in this Special
Issue by Lipavska et al. (2011).
C YC L IN -D EPEN DEN T KI NA SES
Cells are driven from G2 to mitosis upon the activation of a
cyclin-dependent kinase(s) [CDK(s)]. Catalytic activity is conferred on the CDK at various levels through various protein –
protein binding domains and through phosphoregulation of
specific amino acid residues in the CDK (Norbury and
Nurse, 1992). Perhaps the most spectacular event is the
timed synthesis and destruction of the non-catalytic cyclin
that regulates CDK activity. First reported on in sea clams,
mitogenic cyclin rises to a peak of protein concentration at
G2/M and suddenly disappears at early anaphase (Evans
et al., 1983). The binding of the CDK with its partner cyclin
is through phosphorylation of a tyrosine (T160/167) residue
(Krek and Nigg, 1991;Booher et al., 1993). In arabidopsis,
when the cyclin is mutated so that it can no longer be
degraded, mitosis is perfectly normal up to metaphase but
beyond that is a catastrophic meltdown emphasizing just how
important timing of cyclin destruction is to the well-being of
the mitotic cell (Weingartner et al., 2004).
In arabidopsis there are two types of CDK, A and B, that
drive cells into mitosis. The solitary Arath;CDKA;1, first
identified and named, Atcdca (Ferreira et al., 1991) shows
the hall mark features of a classic Cdc2 kinase, a perfectly conserved PSTAIRE domain in its T-loop and CDKA;1 is able to
complement cdc2-/cdc28 mutants of fission/budding yeast.
The B class which proved to be unique to higher plants was
discovered a little later and named Atcdc2b (Joubes et al.,
2000). In arabidopsis, B CDKs comprise Arath;CDKB1;1,
B1;2, B2:1 and B2:2. The B1s and 2s are distinguished from
the A type because PSTAIRE in the conserved domain
shows evolutionary divergence to PPTLARE and PPTLRE,
respectively. Moreover, the B-types are unable to complement
the yeast mutants (Imajuku et al., 1992).
Arabidopsis CDKA1;1 is expressed from S-phase until
mitosis and exhibits two peaks of enzyme activity, at G1/S
and at G2/M (Porceddu et al., 2001). The plant CDKB
family is preferentially expressed in G2 with a solitary peak
of enzyme activity at G2/M (Porceddu et al., 2001; Sorrell
et al., 2001). A gap in current knowledge concerns the exact
kinase profiles of these CDKBs, not to mention their exact substrates and true function.
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Francis — The G2/M transition of the plant cell cycle
CYCLINS
In plants there are over 100 cyclins sharing homology with
the so-called A-, B-, C-, H- and L-types in animals. In arabidopsis there are six classes, A, B, C, D, P and T, although
only cyclins A and B (and D in tobacco BY-2 cells) have
been implicated in the G2/M transition in plants (Dudits
et al., 2007). Whilst much is known about cyclins that
degrade in mitosis (see Weingartner et al., 2004), not that
much is known about the kinetics of synthesis and degradation of other cyclins during the rest of the cell cycle.
To my knowledge, this holds true whatever eukaryote has
been studied.
The generic model is that for a CDK to be active, phosphorylation of a tyrosine residue near the carboxyl terminus of the CDK
(T 160/161/167) is catalysed by a cyclin-dependent activating
kinase (CAK kinase) coincident with cyclin binding (Morgan,
2007). Plant CDK Ds fall into the CAK kinase category. In arabidopsis there is also the class F CDKs that might contribute to
phosphoregulation of the G2/M transition (Shimotohno et al.,
2004). These CDKs are cyclin-dependent activating kinase activating kinases (CAKAKs) but we know very little about their
precise biochemical function in the plant cell cycle. Moreover,
the number of nuclear-housed protein kinases is not limited to
cell cycle CDKs and much more needs to be learned about the
interaction and regulation of this cohort of interacting kinases
(see Dahan et al., 2010).
P H O S P H O R E G U L AT I O N
As has been well documented elsewhere, G2/M CDKs are
negatively regulated by a WEE-like kinase and activated by
CDC25 phosphatase (Featherstone and Russell, 1991;
Russell and Nurse, 1986; Nurse, 1990). In fission yeast,
Wee1/Mik1 act redundantly to phosphorylate tyrosine-15 and
repress Cdc2. Animals have at least one WEE1 kinase (actually one of the human ones shows greater homology to Mik1
than Wee1) and an additional dual threonine-14 tyrosine-15
kinase (MYT1) (Mueller et al., 1995). Thus, the universal
model of cell-cycle control (Nurse, 1990) holds for all major
classes of eukaryotes except for higher plants. In arabidopsis,
a WEE1 has been cloned (Sorrell et al., 2002) but neither
MIK1 nor MYT1 is present in the arabidopsis genome. There
is a small CDC25 in arabidopsis which, seemingly, can flip
between arsenate reductase and protein phosphatase activity
depending on substrate availability (Landrieu et al., 2004;
Bleeker et al., 2006). It lacks the regulatory domain found in
other CDC25s and it is unable to complement temperaturesensitive cdc25-mutants of fission yeast. T-DNA insertional
lines for CDC25 develop normally (Dissmeyer et al., 2009;
Spadafora et al., 2011, this issue) suggesting strongly that
CDC25 plays no part in phoshoregulation at G2/M in plants
grown under normal conditions. However, whatever is physiologically normal for higher plants is an interesting question
and from an ecological perspective, arabidopsis in growth
cabinets is clearly not normal.
Both Arath;WEE1 and Arath;CDC25 can regulate cell size
when inducibly expressed in fission yeast (Sorrell et al., 2002,
2005) and, hence, are capable of regulating the G2/M transition
in a fission yeast genetic background. However, as mentioned
above, T-DNA insertional lines for both WEE1 and CDC25
grow and develop normally (De Schutter et al., 2007;
Spadafora et al., 2011). These findings more or less exclude
these genes having a role at G2/M of a normal cell cycle
unless there is a very wide redundancy for cell cycle phosphatases and kinases at G2/M in plants. The only caveat to this argument is the presence of WEE1 transcripts, protein and kinase
activity that have been detected in higher plants under
‘control’ conditions (Rhee et al., 2003; Lentz Grønlund, 2008;
Malladi and Johnson, 2011). This still begs the question: what,
if anything, is WEE1 doing in ‘normal’ plant cell cycles?
The lack of any obvious mutant phenotype of T-DNA insertional lines, of either WEE1 or CDC25, led Boudolf et al.
(2006) to model G2/M in the absence of phoshoregulation by
CDC25 and WEE1 (Fig. 1). It features CDKA as the protein
kinase that drives cells into mitosis. However, until the cell
is ready for mitosis, this CDK is rendered inactive by an interactor with CDKs (ICKs /KRPS, or CKIs in animals).The mitogenic signal begins when a CDKB phosphorylates the ICK.
Rather like Rb hyperphoshorylation at G1/S (see Murray
et al., 1998), it is hypothesized that phosphorylated ICK1 is
rendered unstable resulting in the release of CDKA which
then drives cells into mitosis. In particular, it’s important to
note that ICK1 only binds to CDKA when the latter is
bound to a partner cyclin (Torres Acosta et al., 2011, this
issue). This implies that binding between CDKA and cyclin
must already be complete prior to binding with ICK1 and
that T14 and Y15 are unphosphorylated; to my knowledge,
there are no data on the kinetics or timing of this aspect of
phoshoregulation in G2/M in higher plants.
A
B
CDKB
CDC25
WEE1
P P
TY
CDK
P
P
ICK
Cyclin
CDKA
Cyclin
F I G . 1. The G2/M transition in plants. (A) an orthodox generic model based
on knowledge from fission yeast, animal and lower plant cell cycles (see text
and Khadaroo et al., 2004). The CDK is bound to its partner cyclin and CDC25
phosphatase (+ve) and WEE1 kinase (– ve) compete for two conserved amino
acid residues, threonine (T) 14 and tyrosine (Y) 15. Removal of the phosphate
(P) groups by CDC25 phosphatase activates the CDK-cyclin complex. (B) A
model that does not depend on phoshoregulation by WEE1 and CDC25.
Instead CDKB (– ve) phosphorylates an interactor with CDKA (ICK) to
remove its –ve regulation of a CDKA–cyclin complex, rendering T14 and
Y15 phosphorylation redundant (see text). Phosphorylation by CDKB of the
ICK destabilizes it thereby activating the CDK–cyclin complex.
Francis — The G2/M transition of the plant cell cycle
Based on a detailed analysis of CDKs at G2/M it might be
that there are molecular circuits in plants which regulate the
G2/M transition in the absence of the classic phosphoregulatory mechanisms exhibited by all other eukaryotes
(Dissmeyer et al., 2009). Alternatively, there might be speciesspecific differences that use different phosphoregulatory circuits for the G2/M transition.
I T M UST B E GR E AT TO BE N OR M AL
As I alluded to earlier, exactly what constitutes normality for a
higher plant? Of course the rider questions would be: for
which plants? which part of the world? coastal or inland? at
which altitude? and so on. For example, what is normal for a
Welsh grassland is most certainly not normal for an
Arizonan cactus. Moreover, to define normality might well
have to take on board knowledge of a huge range of ecological
niches in which plants find themselves. That knowledge is
beyond me! However, I would contend that for most plants
growing, say, in a northern temperate zone lacking an
Oceanic influence, abiotic stress is the norm. Higher plants
are well able to withstand abiotic stress as evidenced by
species growing on rock faces, in deserts and in enormous
extremes of pH. In other words, higher plants have an enormous capacity to close down in conditions such as nutrient
deprivation, drought or waterlogging but remain primed to
exploit the return, however transient, of improved nutrient
availability and favourable temperatures that are more
optimal for both growth and development. At the cell cycle
level, this must mean that plant cells are perfectly able to
remain quiescent until environmental conditions improve to
enable them to proliferate and contribute to a spurt in
growth (see Lipavska et al., 2011, this issue). We might therefore like to think of WEE1, and indeed, ICKC1/2, as part of a
negative surveillance mechanism of the G2/ M transition under
stress conditions. This brings me to cell-cycle checkpoints that
can block cell proliferation under abiotic stress.
The term checkpoint has often been used incorrectly in the
plant cell cycle literature to indicate the G1/S and G2/M transitions. Hartwell and Weinert (1989) first defined a cell-cycle
checkpoint as operating when a step ‘B’ depends on completion
of step ‘A’ unless a loss-function mutant can relieve the dependence. Cells held under checkpoint conditions must be able to
meet the demands imposed by that checkpoint before acquisition
of competence to undergo a cell cycle transition. Experimentally
the DNA-damage checkpoint has been induced by UVB, ionizing radiation or zeocin, a drug that mimics the effects of ionizing
radiation. The DNA-replication checkpoint is usually studied
following treatment with hydroxyurea (HU), a drug that stalls
DNA replication through inhibition of ribonucleotide reductase
(Eklund et al., 2001; Santocanale and Diffley, 2001).
Occasionally, aphidicolin has been used in DNA-replication
checkpoint studies, although I would argue that this drug
neither induces the DNA replication nor DNA-damage checkpoints. Aphidicolin selectively inhibits replicative forms of
DNA polymerase so that cells are unable to undergo the G1/S
transition (Krokan et al., 1981). However, at a concentration of
aphidicolin of 5 mg mL21, DNA is neither damaged nor is its
replication perturbed. Of course any cell afflicted with aphidicolin will stop replicating its DNA, but when the drug is washed
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away those cells are then fully competent to complete DNA
replication and undergo mitosis (see Orchard et al., 2005).
However, no doubt, DNA damage could be inflicted with concentrations in excess of this, as could various other toxins.
As clearly pointed out by O’Connell et al. (1997), eukaryotes possess a latent armoury of genes that are only expressed
under checkpoint conditions. These genes participate in at
least three ( probably more) biochemical pathways designed
to repair DNA or normalize replication but at the same time
prevent these stressed cells from dividing. For example, in
budding yeast, if cells are exposed to ionizing radiation or
HU, RAD3 is expressed; these treatments induce the
DNA-damage and DNA-replication checkpoints, respectively
(al-Khodairy et al., 1994; Elledge, 1996; Abraham et al.,
2000). In mammals and plants, the RAD3 homologues, ATM
and ATR, are similarly induced. These genes encode large
protein kinases that initiate two independent biochemical pathways. In the case of the DNA-damage pathway, the first is a
cascade of DNA-dependent protein kinases that ends in
DNA-repair polymerase(s) that are able to repair single-strand
breaks and, in some cases, double-strand lesions in DNA
(Rhind and Russell, 1998, 2000). The DNA-replication checkpoint (in my view) is a much more subtle checkpoint because
it leads to the induction of enzymes that preferentially overcome the negative regulation imposed by HU, eventually
allowing the DNA to return to its normal path of replication.
Hence, the DNA-replication checkpoint operates independently of the DNA-damage checkpoint in that there is no
cue for the cascade of DNA-dependent kinases and polymerases that are induced by the DNA-damage checkpoint.
This point, in my view, is overlooked by some authors.
Until repair is complete or replication normalized, cells are
prevented from dividing. This suppression of proliferation is
also orchestrated by RAD3/ATM/ATR. In budding yeast,
RAD3 phosphorylates CDS1 in the replication checkpoint
and CHK1 in the damage checkpoint (Rhind and Russell,
1998). In animals, CHK1/2 are dual recipients of a phosphorylation catalysed by either ATM or ATR (Rhind and
Russell, 2000). In arabidopsis, however, the atr mutant is
hypersensitive to HU whilst atm is hypersensitive to zeocin
(Garcia et al., 2003; Culligan et al., 2004). Hence, we see
differential checkpoint pathways induced in higher plants by
HU on the one hand and zeocin on the other.
In animals RAD3 and ATM/ATR are known to phosphorylate checkpoint-like protein kinases (CDS1 and CHK1/2) but
no such kinase has been identified in the plant genome.
CDS1/CHK1/CHK2 phosphorylate CDC25 and WEE1 either
directly in the case of yeasts or indirectly in animals through
alternative pathways involving a polo-like kinase (Branzei
and Foiani, 2008). The recipients of this phosphorylation
cascade react in exactly the opposite way; WEE1 kinase is
up-regulated, or stabilized, whilst CDC25 is down-regulated
(Chen et al., 2003; Boutros et al., 2006). The net effect is
that WEE1 kinase phosphorylates the mitotic CDKs, thereby
preventing cells from dividing. Promiscuous CDC25 activity
that could stimulate aberrant cell division is avoided through
the binding of CDC25 and WEE1 with a partner 14-3-3
protein that effectively protects those phosphorylated residues
(Karlsson-Rosenthal and Millar, 2006). Not only this, different
forms of 14-3-3 proteins also assist in a mechanism that tethers
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Francis — The G2/M transition of the plant cell cycle
CDC25 to the cytoplasm, or steers it to proteolytic degradation, and restricts WEE1 to the nucleus (Dalal et al.,
1999; Rothblum-Oviatt et al., 2001; also see Morgan, 2007).
Hence, animal and yeast cells have an efficient mechanism
that avoids a potential aberrant division.
In plants, either HU or zeocin treatment results in a
transcriptional up-regulation of WEE1 (De Schutter et al.,
2007) and enhanced WEE1 kinase activity (Lentz
Grønlund, 2008). Very recently, increased WEE1 kinase
activity was also detected following zeocin treatment in
Chlamydomonas (K. Bisova, Institute of Microbiology,
Trebon, Czech Republic, pers. comm). So, although we do
not understand the intermediate steps between ATM/ATR
and WEE1, we do know that a primed WEE1 prevents
cell division in much the same way as it does in yeasts
and animals. Moreover, plant WEE1 shows preferential
binding to the 14-3-3, GF14v, and mutation of serine 485
in WEE1 abolished this binding (Lentz Grønlund et al.,
2009); a similarly positioned serine residue is equally
important in mammalian cells. Hence, if we ignore for the
moment the mysterious gap between ATM/ATR and
WEE1, the checkpoint pathway is remarkably conserved in
unrelated eukaryotes. However, Dissmeyer et al. (2009)
provide experimental evidence indicating that WEE1′ s involvement in plant cell-cycle checkpoints might not be through
the conventional phosho-inhibition of tyrosine-15. Their
phoshoproteomic data did not support phoshorylation of
CDKA;1 under checkpoint conditions (see also Boruc
et al., 2010). The CDKB class may be the recipients of
negative phoshoregulation by WEE1 but this is also
doubted by Dissmeyer et al. (2009). They proposed that
WEE1 might act in some other way, like an Mik1 orthologue, targeting proteins other than CDKA for phosphorylation in the plant DNA-damage checkpoint. Whether
WEE1, or indeed MIK1, can undergo conformational
changes to recognize substrates other than G2/M CDKs is
unknown.
However, what about CDC25? The arabidopsis genome
lacks a full-length CDC25, cdc25 knockouts (KOs) develop
normally under controlled conditions and this small CDC25
protein acts as an arsenate reductase when arabidopsis plants
are challenged by arsenate (Bleeker et al., 2006; Dhankher
et al., 2006). This led Dissmeyer et al. (2009) to conclude
that whatever reactivates cell proliferation, once DNA replication is normalized in plants, it does not involve this small
CDC25. Recent data challenge this view. Firstly, animal
CDC25s can exhibit arsenate reductase activity when challenged with arsenate (Bhattacharjee et al., 2010). Hence,
CDC25 can flip between phosphatase and arsenate reductase
activity dependent on substrate. Secondly, T-DNA insertional
lines for CDC25 are hypersensitive to hydroxyurea
(Spadafora et al., 2011). However, the phenotypic response
is quite subtle, roots do not stop growing in the mutant seedlings challenged with HU, they grow more slowly. Hence,
we concluded that CDC25 might be a component but certainly
not the sole activatory signal that enables plants to overcome
the DNA-replication checkpoint. Moreover the cdc25 KOs
were as equally sensitive to zeocin as wild type. This, in our
view, confines CDC25 to the DNA-replication checkpoint.
In animals, the parvulins ( petidyl prolyl cis/trans isomerases) preferentially recognize substrates with phosphorylated serine or threonine residues N-terminal to the proline
residue (Yaffe et al. 1997). These so-called PIN enzymes
interact with a subset of phosphatases involved in cell division
control including CDC25 phosphatase (Crenshaw et al., 1998).
PIN1 expression promotes a structural change in CDC25
(Stukenberg and Kirschner, 2001). In plants a PIN-type
PPIase has been isolated and characterized in arabidopsis
(Landrieu et al., 2000). The arabidopsis PIN1 (it has no
relationship to the auxin-regulated PIN family) featured as a
cell-cycle regulator among a range of plant cell-cycle genes
tested at the RNA transcriptional level using in situ hybridization (de Almeida-Engler et al., 2009). It exhibited a patchy
in situ profile in the root apical meristem, suggesting a tight
cell-cycle control of this gene. If the arabidopsis PIN
enzyme shares features associated with human PIN1, then an
interaction with native CDC25 cannot be entirely eliminated
from the mechanism that operates at the G2/M transition in
the plant cell cycle. Indeed, some sort of functional redundancy at G2/M might (a) explain the normal development of
insertion lines deficient in CDC25 and (b) the participation
of Arath;CDC25 in a novel hyposensitive response upon the
induction by HU of the DNA-replication checkpoint.
One outstanding problem is to reconcile the null response of
cdc25 KOs to HU reported by Dissmeyer et al. (2009) and the
hypersensitivity of these KOs as reported by Spadafora et al.
(2011). The rigour used in both sets of experiments is unquestioned although the environmental conditions used are almost,
by definition, bound to be different. It might well be the case
that differential environmental conditions used in the two sets
of experiments made these KOs differentially sensitive to HU.
I conclude that currently it is impossible to exclude the possibility of CDC25’s involvement in the DNA-replication checkpoint in plants, although time will tell.
Finally, in arabidopsis grown under control conditions, can
the presence of WEE1 transcripts detected in some experiments but their absence in others, even within the same
species be resolved? It seems to me that these apparently
different results are not a million miles away from each
other if it is accepted that in the wild, plants are mostly
under stress. In other words, could it be that in reality plant
checkpoint regulated cell cycles are the norm and meristematic
cells only escape checkpoint conditions when favourable
growth conditions arise?
ACK N OW L E DG E M E N T S
I thank the following colleagues for engaging with me about
cell-cycle checkpoints in plants: Diego Albani (Sardinia,
Italy), John Bryant (Exeter, UK), John Doonan (Norwich,
UK), Hilary Rogers (Cardiff, UK), Andrew West (Leeds, UK)
and former students, Ann Lentz (now in Rothamsted, UK) and
Natasha Spadafora (now in Calabria, Italy). I also thank Stuart
Davies, my Cardiff colleague, and Ian Woodward (Sheffield)
in their fruitless attempts to drag me into the real world of
plants ‘out there!’ However, I accept full responsibility for the
ideas expressed in this short review – for better or for worse.
Francis — The G2/M transition of the plant cell cycle
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