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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. # The Author 2011. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: [email protected] 1066 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 1067 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 1068 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). 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