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Paper text:
the cell cycle , in which cells replicate their genome and then physically divide into daughter cells , is an essential function in keeping multicellular organisms alive and healthy
. however , various environmental factors ( such as ionizing radiation or ultraviolet irradiation , and chemotherapy ) as well as erroneous physiological processes ( such as stalled replication forks or production of reactive oxygen species from metabolic reactions ) cause undesired mutations that can lead to genomic instability and cancer . to prevent transfer of mutations to offspring , cells have evolved checkpoints that sense dna damage and prevent progression through the cell cycle to allow dna repair .
checkpoints are controlled by atm ( ataxia telangiectasia mutated ) and atr ( ataxia telangiectasia and rad3-related protein ) kinases that activate their downstream effector kinases chk2 ( checkpoint kinase 2 ) and chk1 , respectively , and regulate multiple components of the cell cycle control and dna repair pathways .
if the extent of dna damage exceeds the capacity of repair mechanisms , cells are either permanently withdrawn from the cell cycle ( senescence and/or quiescence ) or are eliminated by programmed cell death ( apoptosis ) . however , in most cases dna lesions are successfully repaired and cells re - enter the cell cycle in a process called checkpoint recovery . here
we discuss recent advances in our understanding of checkpoint recovery and its relevance for human cancer .
proliferating cells repeatedly pass through interphase ( consisting of the g1 , s , and g2 phases in which cells grow , replicate dna , and duplicate centrosomes , respectively ) followed by nuclear division ( mitosis ) and cellular division ( cytokinesis ) .
transitions between the phases in the cell cycle are controlled by evolutionarily conserved cyclin - dependent kinases ( cdks ) , which act in complex with various cyclins , the principal regulators of the cell cycle . in the case of the g2/m transition ,
these components are represented by cdk1/cyclin b. interestingly , data from mice genetics indicate that cdk1 is the only essential cdk , because proliferating cells can substitute for loss of any other cdk .
this indicates that the g2/m transition is carefully guarded , probably because an arrest in the g2 checkpoint is the last chance for the cell to prevent transmission of mutations to progeny . as untimely activation of cdk1
can cause premature mitotic entry with deleterious consequences , activity of cdk1 is carefully regulated at multiple levels ( see figure 1 ) .
first , cyclin b levels are low in g1 and gradually increase in g2 , just before cells need to activate cdk1 to promote mitotic entry .
second , wee1 and myt1 kinases directly inhibit cdk1 by phosphorylating its thr-14 and tyr-15 residues .
removal of these inhibitory modifications is controlled by members of the cdc25 ( cell division cycle 25 ) family of phosphatases and leads to a rapid activation of cdk1/cyclin b. finally , an initial activation of cdk1/cyclin b stimulates the activity of cdc25 and inactivates wee1 , creating two feedback loops that result in a switch - like activation of cdk1 .
activation of the dna damage checkpoint in the g2 phase leads to increased activation of wee1 as well as to degradation of cdc25a , inhibition of cdc25b , or cytosolic sequestration of cdc25c , which all contribute to keeping cdk1 activity low and preventing mitotic entry . during checkpoint recovery ,
cells rely on plk1 ( polo - like kinase 1 ) , which targets both wee1 and claspin ( an essential cofactor of atr ) for proteasomal degradation [ 9 - 12 ] .
plk1 also promotes nuclear translocation of cdc25c   and directly inhibits chk2 and the p53 binding protein 53bp1 .
interestingly , plk1 activity is redundant in unperturbed mitotic entry whereas it becomes essential in checkpoint recovery , and this function is conserved in organisms ranging from yeast to humans .
activity of plk1 is low after dna damage whereas it becomes fully active during checkpoint recovery .
phosphorylation within the t - loop of plk1 is driven by aurora - a kinase in complex with an adaptor protein , hbora , and is essential for activation of plk1 and for checkpoint recovery .
apart from its role in recovery , the yeast plk1 homolog cdc5 is indispensable for adaptation to irreparable dna damage ; however , it remains unclear whether this pathway is conserved also in higher eukaryotes .
g2 : the activity of pp2a outweighs the capacity of cyclin b / cdk1 to phosphorylate its substrates .
activity of cyclin b / cdk1 is very low due to inhibitory phosphorylation by wee1 and myt1 ( yellow circles ) .
following dephosphorylation of cdk1 by cdc25a / b / c , cyclin b / cdk1 is activated . through greatwall
, it inhibits pp2a , and by phosphorylation of multiple substrates , it initiates mitotic entry .
dna damage : the cell remains arrested at the g2 checkpoint and cyclin b / cdk1 is kept in an inactive state by wee1 and by transcriptional repression of cyclin b by p53 .
basal activities of foxm1 and wip1 ( gray circle ) prevent cyclin b levels from dropping below a threshold during the checkpoint .
checkpoint recovery : after successful dna repair , the checkpoint is switched off by fully activated wip1 phosphatase and plk1 kinase , both contributing to activation of cyclin b / cdk1 and enabling checkpoint recovery .
atm , ataxia telangiectasia mutated ; atr , ataxia telangiectasia and rad3-related protein ; aura , aurora kinase a ; cdc25a / b / c , cell division cycle 25a , b and c ; cdk1 , cyclin - dependent kinase 1 ; chk1/2 , checkpoint kinase 1 and 2 ; ensa , -endosulfine ; foxm1 , forkhead box protein m1 ; hbora , human bora ; plk1 , polo - like kinase 1 ; pp2a , protein phosphatase 2a ; wip1 , wild - type p53-induced phosphatase 1 .
although plk1 activity is essential for recovery , it is not sufficient , indicating that additional control mechanisms exist .
as dna damage response pathways mostly rely on phosphorylation of multiple substrates , phosphatases that counteract such modifications are likely candidates to be involved in silencing the checkpoint and promoting checkpoint recovery .
this was borne out in a study showing that two members of the protein phosphatase 2c ( pp2c ) family , ptc2 and ptc3 , are necessary for checkpoint recovery in yeast . in mammals
, it was suggested that multiple phosphatases participate in inhibition of the dna damage response pathway . among these ,
wild - type p53-induced phosphatase 1 ( wip1 ; also called pp2c - delta or ppm1d ) seems to play a central role because it specifically recognizes a p(s / t)q motif , phosphorylated mostly by atm / atr kinases , allowing wip1 to efficiently dephosphorylate multiple players in the dna damage response pathway .
although wip1 dephosphorylates many targets , the most relevant for checkpoint recovery is probably the tumor suppressor p53 .
the presence of wip1 throughout the checkpoint counteracts the function of p53 as a transcriptional repressor of mitotic inducers   and thus allows levels of cyclin b and plk1 to be kept high enough for eventual checkpoint recovery following successful repair of damaged dna .
apart from a direct dephosphorylation of pser15 on p53 , wip1 has been shown to decrease p53 levels by activating the ubiquitin e3 ligase mdm2 , which targets p53 for proteasomal degradation , and also through activation of mdmx , which directly inhibits transcriptional activity of p53 at promoters . determining which one of these mechanisms is the most physiologically relevant still remains unaccomplished
; however , counteracting the p53 function seems to be the major role for wip1 .
this view is further supported by finding high expression levels of wip1 in tumors that do not have inactivating mutations in p53 .
conversely , overexpression of wip1 is very rare in tumors carrying mutations in p53 , possibly because the selection pressure for amplification of the wip1 locus was lost by inactivating p53 .
it appears that apart from mechanisms regulating cdk1/cyclin b activity as described above , cells also actively control the outcome of cdk1 activation at the level of its multiple substrates .
this is achieved by pp2a - b55 phosphatase , which actively reverses phosphorylations made by cdk during the interphase and thus prevents premature mitotic entry .
strikingly , the activity of pp2a - b55 is inhibited by a greatwall kinase ( called mast - l [ microtubule - associated serine / threonine - protein kinase - like ] in humans ) that is active in mitosis and ensures that cells pass through mitosis with full phosphorylation of cdk1 substrates [ 27 - 29 ] .
recently it has been demonstrated that this is achieved by phosphorylation of a pp2a inhibitor , arpp19/ensa ( camp - regulated phosphoprotein 19/-endosulfine ) , by greatwall .
importantly , greatwall is activated in mitosis through phosphorylation by cdk1/cyclin b , and once phosphorylated , forms a negative feedback loop to pp2a . in light of these new findings , one can think of the g2/m transition as a balance between cdk1/cyclin b activity and activity of the opposing pp2a phosphatase . in the normal cell cycle ,
conversely , checkpoint mechanisms block the activation of cdk1 which may push the balance towards activity of pp2a and prevent mitotic entry .
this would imply that cells that repair dna lesions and enter mitosis through a checkpoint recovery pathway need to overcome a higher barrier generated by pp2a than undamaged cells .
this suggests that additional mechanisms ( such as the activity of plk1 ) are likely to be required for checkpoint recovery to support cdk1 in the fight against the phosphatase - induced barrier .
moreover , prolonged arrest in the g2 checkpoint leads to activation of p53 , which causes a drop in levels of cyclin b and plk1 and further lowers the capacity of cells to recover .
it appears that cells held at the g2 checkpoint adopt mechanisms ( such as activating wip1 to counteract the effect of p53 ) that prevent a drop of mitotic - inducing activity below a certain threshold and retain competence for eventual recovery .
this model is further supported by a recent finding that cells need to maintain a basal level of cdk activity during a dna damage - induced g2 arrest in order to recover .
this enables cells to retain the transcriptional activity of the proliferation - promoting forkhead box protein foxm1 throughout the dna damage and allows them to sustain high levels of cyclin b .
how the basal activity of cdk1 is regulated throughout the dna damage , however , still remains to be elucidated .
an attractive possibility is that greatwall inhibition during the dna damage response allows pp2a to reduce the phosphorylation level of some cdk substrates ( leaving the basal cdk1 activity untouched ) .
alternatively , pp2a might only target substrates of some cdks , perhaps leaving substrates of cdk2/cyclin a ( including foxm1 ) phosphorylated whereas acting preferentially on cdk1 substrates .
probably the most clinically relevant mode of dna damage is represented by the genotoxic stress caused by radiotherapy or chemotherapy routinely used to cure cancer .
both strategies rely on induction of a cell death or permanent cell cycle arrest of tumor cells exposed to dna damage , but at the same time they are limited by their toxic effects on normal tissues . with the recent major advances in understanding the molecular functioning of cell cycle checkpoints
, it is hoped that in the future it may be possible to pharmacologically target components of the checkpoint recovery pathway , which may increase the sensitivity of tumor cells to current treatments .
dysregulation of the cell cycle is the underlying mechanism of neoplasia . 
 healthy cells prevent propagation of dna mutations to progeny by activation of cellular checkpoints , which allows time for dna repair . on the other hand , activation of the dna damage response 
 is also the general principle of many current cancer treatments . 
 thus , recent advances in understanding how checkpoints in the cell cycle work at the molecular level open the door to new approaches to antitumor therapy .