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CellcycleWikipedia

Cellcycle
FromWikipedia,thefreeencyclopedia

ThecellcycleorcelldivisioncycleistheseriesofeventsthattakeplaceinacellleadingtoitsdivisionandduplicationofitsDNA
(DNAreplication)toproducetwodaughtercells.Inbacteria,whichlackacellnucleus,thecellcycleisdividedintotheB,C,andD
periods.TheBperiodextendsfromtheendofcelldivisiontothebeginningofDNAreplication.DNAreplicationoccursduringtheC
period.TheDperiodreferstothestagebetweentheendofDNAreplicationandthesplittingofthebacterialcellintotwodaughter
cells.[2]Incellswithanucleus,asineukaryotes,thecellcycleisalsodividedintothreeperiods:interphase,themitotic(M)phase,and
cytokinesis.Duringinterphase,thecellgrows,accumulatingnutrientsneededformitosis,preparingitforcelldivisionandduplicating
itsDNA.Duringthemitoticphase,thechromosomesseparate.Duringthefinalstage,cytokinesis,thechromosomesandcytoplasm
separateintotwonewdaughtercells.Toensuretheproperdivisionofthecell,therearecontrolmechanismsknownascellcycle
checkpoints.

LifeCycleofthecell

Thecelldivisioncycleisavitalprocessbywhichasinglecelledfertilizedeggdevelopsintoamatureorganism,aswellastheprocess
bywhichhair,skin,bloodcells,andsomeinternalorgansarerenewed.Aftercelldivision,eachofthedaughtercellsbegintheinterphaseofa
newcycle.Althoughthevariousstagesofinterphasearenotusuallymorphologicallydistinguishable,eachphaseofthecellcyclehasadistinct
setofspecializedbiochemicalprocessesthatpreparethecellforinitiationofcelldivision.

Contents
1 Cellcyclephases
1.1 G0phase(Quiescence)
1.2 Interphase(Intermitosis)
1.2.1 G1Phase(Growth)
1.2.2 SPhase(DNAreplication)
1.2.3 G2Phase(Growth)
1.3 Mitoticphase(Chromosomeseparation)
1.4 Cytokinesisphase(Separationofallcellcomponents)
2 Regulationofeukaryoticcellcycle
2.1 RoleofcyclinsandCDKs
2.1.1 GeneralmechanismofcyclinCDKinteraction
2.1.2 SpecificactionofcyclinCDKcomplexes
2.2 Inhibitors
2.3 Transcriptionalregulatorynetwork
2.4 DNAreplicationandDNAreplicationoriginactivity
3 Checkpoints
4 Fluorescenceimagingofthecellcycle
https://en.wikipedia.org/wiki/Cell_cycle

Schematicofthecell
cycle.outerring:I=
Interphase,M=Mitosis
innerring:M=Mitosis,
G1=Gap1,G2=Gap2,
S=Synthesisnotin
ring:G0=Gap
0/Resting. [1]

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Roleintumorformation
Seealso
References
Furtherreading
Externallinks

Cellcyclephases

https://en.wikipedia.org/wiki/Cell_cycle

Onion(Allium)cellsin
differentphasesofthe
cellcycle.Growthinan
organismiscarefully
controlledbyregulating
thecellcycle.

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State

CellcycleWikipedia

Description Abbreviation
Gap0

Quiescent
senescent/resting
phase
Interphase

Gap2

Celldivision

Mitosis

G0

:
Arestingphasewherethecellhasleftthecycleandhas
stoppeddividing.Cellcyclestartswiththisphase.

Gap1

G1

CellsincreaseinsizeinGap1.TheG1checkpointcontrol
mechanismensuresthateverythingisreadyforDNA
synthesis.

Synthesis

DNAreplicationoccursduringthisphase.

G2

DuringthegapbetweenDNAsynthesisandmitosis,thecell
willcontinuetogrow.TheG2checkpointcontrolmechanism
ensuresthateverythingisreadytoentertheM(mitosis)
phaseanddivide.

Cellgrowthstopsatthisstageandcellularenergyisfocused
ontheorderlydivisionintotwodaughtercells.Acheckpoint
inthemiddleofmitosis(MetaphaseCheckpoint)ensures
thatthecellisreadytocompletecelldivision.

G0phase(Quiescence)
G0isarestingphasewherethecellhasleftthecycleandhasstoppeddividing.Thecellcyclestartswiththisphase.Theword
"postmitotic"issometimesusedtorefertobothquiescentandsenescentcells.Nonproliferative(nondividing)cellsin
multicellulareukaryotesgenerallyenterthequiescentG0statefromG1andmayremainquiescentforlongperiodsoftime,possibly
indefinitely(asisoftenthecaseforneurons).Thisisverycommonforcellsthatarefullydifferentiated.Cellularsenescence(death)
occursinresponsetoDNAdamageordegradationthatwouldmakeacell'sprogenynonviable.SomecellsentertheG0phasesemi
permanentlye.g.,someliver,kidney,stomachcells.ManycellsdonotenterG0andcontinuetodividethroughoutanorganism's
life,e.g.epithelialcells.

Interphase(Intermitosis)
Plantcellcycle

Beforeacellcanentercelldivision,itneedstotakeinnutrients.Allofthepreparationsaredoneduringinterphase.Interphaseisa
seriesofchangesthattakesplaceinanewlyformedcellanditsnucleus,beforeitbecomescapableofdivisionagain.Itisalso
calledpreparatoryphaseorintermitosis.Previouslyitwascalledrestingstagebecausethereisnoapparentactivityrelatedtocelldivision.Typicallyinterphaselastsforat
least90%ofthetotaltimerequiredforthecellcycle.
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Interphaseproceedsinthreestages,G1,S,andG2,followedbythecycleofmitosisandcytokinesis.Thecell'snuclear
chromosomesareduplicatedduringSphase.
G1Phase(Growth)
Thefirstphasewithininterphase,fromtheendofthepreviousMphaseuntilthebeginningofDNAsynthesis,iscalledG1(G
indicatinggap).Itisalsocalledthegrowthphase.Duringthisphase,thebiosyntheticactivitiesofthecell,whichareconsiderably
sloweddownduringMphase,resumeatahighrate.ThedurationofG1ishighlyvariable,evenamongdifferentcellsofthesame
species.Inthisphase,thecellincreasesitssupplyofproteins,increasesthenumberoforganelles(suchasmitochondria,
ribosomes),andgrowsinsize.
SPhase(DNAreplication)

Animalcellcycle

TheensuingSphasestartswhenDNAreplicationcommenceswhenitiscompleted,allofthechromosomeshavebeenreplicated,i.e.,eachchromosomehastwo(sister)
chromatids.Thus,duringthisphase,theamountofDNAinthecellhaseffectivelydoubled,thoughtheploidyofthecellremainsthesame.Duringthisphase,synthesisis
completedasquicklyaspossibleduetotheexposedbasepairsbeingsensitivetoharmfulexternalfactorssuchasmutagens.
G2Phase(Growth)
G2phaseisaperiodofproteinsynthesisandrapidcellgrowthtopreparethecellformitosis.

Mitoticphase(Chromosomeseparation)
TherelativelybriefMphaseconsistsofnucleardivision(karyokinesis).Itisarelativelyshortperiodofthecellcycle.Mphaseiscomplexandhighlyregulated.The
sequenceofeventsisdividedintophases,correspondingtothecompletionofonesetofactivitiesandthestartofthenext.Thesephasesaresequentiallyknownas:
prophase,
metaphase,
anaphase,
telophase
Mitosisistheprocessbywhichaeukaryoticcellseparatesthechromosomesinitscellnucleusintotwoidenticalsetsintwonuclei.[3]Duringtheprocessofmitosisthe
pairsofchromosomescondenseandattachtofibersthatpullthesisterchromatidstooppositesidesofthecell.[4]
Mitosisoccursexclusivelyineukaryoticcells,butoccursindifferentwaysindifferentspecies.Forexample,animalsundergoan"open"mitosis,wherethenuclear
envelopebreaksdownbeforethechromosomesseparate,whilefungisuchasAspergillusnidulansandSaccharomycescerevisiae(yeast)undergoa"closed"mitosis,where
chromosomesdividewithinanintactcellnucleus.[5]Prokaryoticcells,whichlackanucleus,dividebyaprocesscalledbinaryfission.
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Cytokinesisphase(Separationofallcellcomponents)
Mitosisisimmediatelyfollowedbycytokinesis,whichdividesthenuclei,cytoplasm,organellesandcellmembraneintotwocellscontainingroughlyequalsharesofthese
cellularcomponents.Mitosisandcytokinesistogetherdefinethedivisionofthemothercellintotwodaughtercells,geneticallyidenticaltoeachotherandtotheirparent
cell.Thisaccountsforapproximately10%ofthecellcycle.
Becausecytokinesisusuallyoccursinconjunctionwithmitosis,"mitosis"isoftenusedinterchangeablywith"Mphase".However,therearemanycellswheremitosisand
cytokinesisoccurseparately,formingsinglecellswithmultiplenucleiinaprocesscalledendoreplication.Thisoccursmostnotablyamongthefungiandslimemoulds,but
isfoundinvariousgroups.Eveninanimals,cytokinesisandmitosismayoccurindependently,forinstanceduringcertainstagesoffruitflyembryonicdevelopment.[6]
Errorsinmitosiscaneitherkillacellthroughapoptosisorcausemutationsthatmayleadtocancer.

Regulationofeukaryoticcellcycle
Regulationofthecellcycleinvolvesprocessescrucialtothesurvivalofacell,includingthedetectionand
repairofgeneticdamageaswellasthepreventionofuncontrolledcelldivision.Themoleculareventsthat
controlthecellcycleareorderedanddirectionalthatis,eachprocessoccursinasequentialfashionanditis
impossibleto"reverse"thecycle.

RoleofcyclinsandCDKs
Twokeyclassesofregulatorymolecules,cyclinsandcyclindependentkinases
(CDKs),determineacell'sprogressthroughthecellcycle.[7]LelandH.Hartwell,
R.TimothyHunt,andPaulM.Nursewonthe2001NobelPrizeinPhysiologyor
Medicinefortheirdiscoveryofthesecentralmolecules.[8]Manyofthegenes
encodingcyclinsandCDKsareconservedamongalleukaryotes,butingeneral
morecomplexorganismshavemoreelaboratecellcyclecontrolsystemsthat
incorporatemoreindividualcomponents.Manyoftherelevantgeneswerefirst
identifiedbystudyingyeast,especiallySaccharomycescerevisiae[9]genetic
nomenclatureinyeastdubsmanyofthesegenescdc(for"celldivisioncycle")
followedbyanidentifyingnumber,e.g.cdc25orcdc20.
NobelLaureatePaul
Nurse

CyclinsformtheregulatorysubunitsandCDKsthecatalyticsubunitsofan
activatedheterodimercyclinshavenocatalyticactivityandCDKsareinactivein
theabsenceofapartnercyclin.Whenactivatedbyaboundcyclin,CDKsperform
acommonbiochemicalreactioncalledphosphorylationthatactivatesorinactivatestargetproteinsto
orchestratecoordinatedentryintothenextphaseofthecellcycle.DifferentcyclinCDKcombinations
determinethedownstreamproteinstargeted.CDKsareconstitutivelyexpressedincellswhereascyclinsare
synthesisedatspecificstagesofthecellcycle,inresponsetovariousmolecularsignals.[10]
https://en.wikipedia.org/wiki/Cell_cycle

Lifetimeline
viewdiscuss

P
h
a
n
500 r
z
c

Flowers
Mammals
Dinosaurs

Landlife

Cambrianexplosion
Multicellular
life

1000

Earliestsexual

P
1500

2000

r
o
t
e
r
o
z
o
i
c

reproduction

Eukaryotes
OxygenCrisis
Atmosphericoxygen

2500

Earliesthumans

A
r

3000 c

h
e
a

photosynthesis

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GeneralmechanismofcyclinCDKinteraction
Uponreceivingapromitoticextracellularsignal,G1cyclinCDKcomplexesbecomeactivetopreparethecell
forSphase,promotingtheexpressionoftranscriptionfactorsthatinturnpromotetheexpressionofScyclins
andofenzymesrequiredforDNAreplication.TheG1cyclinCDKcomplexesalsopromotethedegradationof
moleculesthatfunctionasSphaseinhibitorsbytargetingthemforubiquitination.Onceaproteinhasbeen
ubiquitinated,itistargetedforproteolyticdegradationbytheproteasome.However,resultsfromarecent
studyofE2FtranscriptionaldynamicsatthesinglecelllevelarguethattheroleofG1cyclinCDKactivities,
inparticularcyclinDCDK4/6,istotunethetimingratherthanthecommitmentofcellcycleentry.[11]

e
3500

a
n

Earliestoxygen
Singlecelled
life

4000 H
a
d
e
a
4500 n

LHBmeteorites
Earliestlife

water

(4100)

Earliestwater
EarliestEarth
Axisscale:millionsofyears.
(4540)

alsosee{{Humantimeline}}and{{Naturetimeline}}

ActiveScyclinCDKcomplexesphosphorylateproteinsthatmakeuptheprereplicationcomplexes
assembledduringG1phaseonDNAreplicationorigins.Thephosphorylationservestwopurposes:toactivateeachalreadyassembledprereplicationcomplex,andto
preventnewcomplexesfromforming.Thisensuresthateveryportionofthecell'sgenomewillbereplicatedonceandonlyonce.Thereasonforpreventionofgapsin
replicationisfairlyclear,becausedaughtercellsthataremissingallorpartofcrucialgeneswilldie.However,forreasonsrelatedtogenecopynumbereffects,possession
ofextracopiesofcertaingenesisalsodeleterioustothedaughtercells.
MitoticcyclinCDKcomplexes,whicharesynthesizedbutinactivatedduringSandG2phases,promotetheinitiationofmitosisbystimulatingdownstreamproteins
involvedinchromosomecondensationandmitoticspindleassembly.Acriticalcomplexactivatedduringthisprocessisaubiquitinligaseknownastheanaphase
promotingcomplex(APC),whichpromotesdegradationofstructuralproteinsassociatedwiththechromosomalkinetochore.APCalsotargetsthemitoticcyclinsfor
degradation,ensuringthattelophaseandcytokinesiscanproceed.[12]
SpecificactionofcyclinCDKcomplexes
CyclinDisthefirstcyclinproducedinthecellcycle,inresponsetoextracellularsignals(e.g.growthfactors).CyclinDbindstoexistingCDK4,formingtheactivecyclin
DCDK4complex.CyclinDCDK4complexinturnphosphorylatestheretinoblastomasusceptibilityprotein(Rb).ThehyperphosphorylatedRbdissociatesfromthe
E2F/DP1/Rbcomplex(whichwasboundtotheE2Fresponsivegenes,effectively"blocking"themfromtranscription),activatingE2F.ActivationofE2Fresultsin
transcriptionofvariousgeneslikecyclinE,cyclinA,DNApolymerase,thymidinekinase,etc.CyclinEthusproducedbindstoCDK2,formingthecyclinECDK2
complex,whichpushesthecellfromG1toSphase(G1/S,whichinitiatestheG2/Mtransition).[13]CyclinBcdk1complexactivationcausesbreakdownofnuclear
envelopeandinitiationofprophase,andsubsequently,itsdeactivationcausesthecelltoexitmitosis.[10]
AquantitativestudyofE2Ftranscriptionaldynamicsatthesinglecelllevelbyusingengineeredfluorescentreportercellsprovidedaquantitativeframeworkfor
understandingthecontrollogicofcellcycleentry,challengingthecanonicaltextbookmodel.GenesthatregulatetheamplitudeofE2Faccumulation,suchasMyc,
determinethecommitmentintocellcycleandSphaseentry.G1cyclinCDKactivitiesarenotthedriverofcellcycleentry.Instead,theyprimarilytunethetimingofE2F
increase,therebymodulatingthepaceofcellcycleprogression.[11]

Inhibitors
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Twofamiliesofgenes,thecip/kip(CDKinteractingprotein/Kinaseinhibitoryprotein)familyandtheINK4a/ARF
(InhibitorofKinase4/AlternativeReadingFrame)family,preventtheprogressionofthecellcycle.Becausethesegenes
areinstrumentalinpreventionoftumorformation,theyareknownastumorsuppressors.
Thecip/kipfamilyincludesthegenesp21,p27andp57.TheyhaltcellcycleinG1phase,bybindingto,and
inactivating,cyclinCDKcomplexes.p21isactivatedbyp53(which,inturn,istriggeredbyDNAdamagee.g.dueto
radiation).p27isactivatedbyTransformingGrowthFactorof(TGF),agrowthinhibitor.
TheINK4a/ARFfamilyincludesp16INK4a,whichbindstoCDK4andarreststhecellcycleinG1phase,andp14ARF
whichpreventsp53degradation.
SyntheticinhibitorsofCdc25couldalsobeusefulforthearrestofcellcycleandthereforebeusefulasantineoplastic
andanticanceragents.[14]

Transcriptionalregulatorynetwork

Overviewofsignaltransductionpathwaysinvolved
inapoptosis,alsoknownas"programmedcell
death".

CurrentevidencesuggeststhatasemiautonomoustranscriptionalnetworkactsinconcertwiththeCDKcyclinmachinerytoregulatethecellcycle.Severalgene
expressionstudiesinSaccharomycescerevisiaehaveidentified8001200genesthatchangeexpressionoverthecourseofthecellcycle.[9][15][16]Theyaretranscribedat
highlevelsatspecificpointsinthecellcycle,andremainatlowerlevelsthroughouttherestofthecycle.Whilethesetofidentifiedgenesdiffersbetweenstudiesdueto
thecomputationalmethodsandcriteriausedtoidentifythem,eachstudyindicatesthatalargeportionofyeastgenesaretemporallyregulated.[17]
Manyperiodicallyexpressedgenesaredrivenbytranscriptionfactorsthatarealsoperiodicallyexpressed.Onescreenofsinglegeneknockoutsidentified48transcription
factors(about20%ofallnonessentialtranscriptionfactors)thatshowcellcycleprogressiondefects.[18]Genomewidestudiesusinghighthroughputtechnologieshave
identifiedthetranscriptionfactorsthatbindtothepromotersofyeastgenes,andcorrelatingthesefindingswithtemporalexpressionpatternshaveallowedthe
identificationoftranscriptionfactorsthatdrivephasespecificgeneexpression.[15][19]Theexpressionprofilesofthesetranscriptionfactorsaredrivenbythetranscription
factorsthatpeakinthepriorphase,andcomputationalmodelshaveshownthataCDKautonomousnetworkofthesetranscriptionfactorsissufficienttoproducesteady
stateoscillationsingeneexpression).[16][20]
ExperimentalevidencealsosuggeststhatgeneexpressioncanoscillatewiththeperiodseenindividingwildtypecellsindependentlyoftheCDKmachinery.Orlandoetal.
usedmicroarraystomeasuretheexpressionofasetof1,271genesthattheyidentifiedasperiodicinbothwildtypecellsandcellslackingallSphaseandmitoticcyclins
(clb1,2,3,4,5,6).Ofthe1,271genesassayed,882continuedtobeexpressedinthecyclindeficientcellsatthesametimeasinthewildtypecells,despitethefactthatthe
cyclindeficientcellsarrestattheborderbetweenG1andSphase.However,833ofthegenesassayedchangedbehaviorbetweenthewildtypeandmutantcells,indicating
thatthesegenesarelikelydirectlyorindirectlyregulatedbytheCDKcyclinmachinery.Somegenesthatcontinuedtobeexpressedontimeinthemutantcellswerealso
expressedatdifferentlevelsinthemutantandwildtypecells.ThesefindingssuggestthatwhilethetranscriptionalnetworkmayoscillateindependentlyoftheCDKcyclin
oscillator,theyarecoupledinamannerthatrequiresbothtoensurethepropertimingofcellcycleevents.[16]Otherworkindicatesthatphosphorylation,apost
translationalmodification,ofcellcycletranscriptionfactorsbyCdk1mayalterthelocalizationoractivityofthetranscriptionfactorsinordertotightlycontroltimingof
targetgenes.[18][21][22]
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Whileoscillatorytranscriptionplaysakeyroleintheprogressionoftheyeastcellcycle,theCDKcyclinmachineryoperatesindependentlyintheearlyembryoniccell
cycle.Beforethemidblastulatransition,zygotictranscriptiondoesnotoccurandallneededproteins,suchastheBtypecyclins,aretranslatedfrommaternallyloaded
mRNA.[23]

DNAreplicationandDNAreplicationoriginactivity
AnalysesofsynchronizedculturesofSaccharomycescerevisiaeunderconditionsthatpreventDNAreplicationinitiationwithoutdelayingcellcycleprogressionshowed
thatoriginlicensingdecreasestheexpressionofgeneswithoriginsneartheir3'ends,revealingthatdownstreamoriginscanregulatetheexpressionofupstreamgenes.[24]
ThisconfirmspreviouspredictionsfrommathematicalmodelingofaglobalcausalcoordinationbetweenDNAreplicationoriginactivityandmRNAexpression,[25][26][27]
andshowsthatmathematicalmodelingofDNAmicroarraydatacanbeusedtocorrectlypredictpreviouslyunknownbiologicalmodesofregulation.

Checkpoints
Cellcyclecheckpointsareusedbythecelltomonitorandregulatetheprogressofthecellcycle.[28]Checkpointspreventcellcycleprogressionatspecificpoints,allowing
verificationofnecessaryphaseprocessesandrepairofDNAdamage.Thecellcannotproceedtothenextphaseuntilcheckpointrequirementshavebeenmet.Checkpoints
typicallyconsistofanetworkofregulatoryproteinsthatmonitoranddictatetheprogressionofthecellthroughthedifferentstagesofthecellcycle.
ThereareseveralcheckpointstoensurethatdamagedorincompleteDNAisnotpassedontodaughtercells.Threemaincheckpointsexist:theG1/Scheckpoint,theG2/M
checkpointandthemetaphase(mitotic)checkpoint.
G1/Stransitionisaratelimitingstepinthecellcycleandisalsoknownasrestrictionpoint.[10]Thisiswherethecellcheckswhetherithasenoughrawmaterialstofully
replicateitsDNA(nucleotidebases,DNAsynthase,chromatin,etc.).Anunhealthyormalnourishedcellwillgetstuckatthischeckpoint.
TheG2/Mcheckpointiswherethecellensuresthatithasenoughcytoplasmandphospholipidsfortwodaughtercells.Butsometimesmoreimportantly,itcheckstoseeif
itistherighttimetoreplicate.Therearesomesituationswheremanycellsneedtoallreplicatesimultaneously(forexample,agrowingembryoshouldhaveasymmetric
celldistributionuntilitreachesthemidblastulatransition).ThisisdonebycontrollingtheG2/Mcheckpoint.
Themetaphasecheckpointisafairlyminorcheckpoint,inthatonceacellisinmetaphase,ithascommittedtoundergoingmitosis.Howeverthat'snottosayitisn't
important.Inthischeckpoint,thecellcheckstoensurethatthespindlehasformedandthatallofthechromosomesarealignedatthespindleequatorbeforeanaphase
begins.[29]
Whilethesearethethree"main"checkpoints,notallcellshavetopassthrougheachofthesecheckpointsinthisordertoreplicate.Manytypesofcancerarecausedby
mutationsthatallowthecellstospeedthroughthevariouscheckpointsorevenskipthemaltogether.GoingfromStoMtoSphasealmostconsecutively.Becausethese
cellshavelosttheircheckpoints,anyDNAmutationsthatmayhaveoccurredaredisregardedandpassedontothedaughtercells.Thisisonereasonwhycancercellshave
atendencytoexponentiallyaccruemutations.Asidefromcancercells,manyfullydifferentiatedcelltypesnolongerreplicatesotheyleavethecellcycleandstayinG0
untiltheirdeath.Thusremovingtheneedforcellularcheckpoints.AnalternativemodelofthecellcycleresponsetoDNAdamagehasalsobeenproposed,knownasthe
postreplicationcheckpoint.
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Checkpointregulationplaysanimportantroleinanorganism'sdevelopment.Insexualreproduction,wheneggfertilizationoccurs,whenthespermbindstotheegg,it
releasessignallingfactorsthatnotifytheeggthatithasbeenfertilized.Amongotherthings,thisinducesthenowfertilizedoocytetoreturnfromitspreviouslydormant,
G0,statebackintothecellcycleandontomitoticreplicationanddivision.
p53playsanimportantroleintriggeringthecontrolmechanismsatbothG1/SandG2/Mcheckpoints.Inadditiontop53,checkpointregulatorsarebeingheavily
researchedfortheirrolesincancergrowthandproliferation.

Fluorescenceimagingofthecellcycle
PioneeringworkbyAtsushiMiyawakiandcoworkersdevelopedthefluorescentubiquitinationbasedcellcycleindicator(FUCCI(http://www.
conncoll.edu/ccacad/zimmer/GFPww/cooluses19.html)),whichenablesfluorescenceimagingofthecellcycle.Originally,agreenfluorescent
protein,mAG,wasfusedtohGem(1/110)andanorangefluorescentprotein(mKO2)wasfusedtohCdt1(30/120).Note,thesefusionsare
fragmentsthatcontainanuclearlocalizationsignalandubiquitinationsitesfordegradation,butarenotfunctionalproteins.Thegreen
fluorescentproteinismadeduringtheS,G2,orMphaseanddegradedduringtheG0orG1phase,whiletheorangefluorescentproteinismade
duringtheG0orG1phaseanddestroyedduringtheS,G2,orMphase.[30]AfarredandnearinfraredFUCCIwasdevelopedusinga
cyanobacteriaderivedfluorescentprotein(smURFP)andabacteriophytochromederivedfluorescentprotein(moviefoundatthislink(http://w
ww.nature.com/nmeth/journal/vaop/ncurrent/fig_tab/nmeth.3935_SV2.html)).[31]

Roleintumorformation
Adisregulationofthecellcyclecomponentsmayleadtotumorformation.[32]Asmentionedabove,whensomegeneslikethecellcycle
inhibitors,RB,p53etc.mutate,theymaycausethecelltomultiplyuncontrollably,formingatumor.Althoughthedurationofcellcyclein
tumorcellsisequaltoorlongerthanthatofnormalcellcycle,theproportionofcellsthatareinactivecelldivision(versusquiescentcellsin
G0phase)intumorsismuchhigherthanthatinnormaltissue.Thusthereisanetincreaseincellnumberasthenumberofcellsthatdieby
apoptosisorsenescenceremainsthesame.

Fluorescentproteins
visualizethecellcycle
progression.IFP2.0
hGem(1/110)
fluorescenceisshownin
greenandhighlightsthe
S/G2/Mphases.
smURFPhCdtI(30/120)
fluorescenceisshownin
redandhighlightsthe
G0/G1phases.

ThecellswhichareactivelyundergoingcellcyclearetargetedincancertherapyastheDNAisrelativelyexposedduringcelldivisionand
hencesusceptibletodamagebydrugsorradiation.Thisfactismadeuseofincancertreatmentbyaprocessknownasdebulking,asignificant
massofthetumorisremovedwhichpushesasignificantnumberoftheremainingtumorcellsfromG0toG1phase(duetoincreasedavailabilityofnutrients,oxygen,
growthfactorsetc.).Radiationorchemotherapyfollowingthedebulkingprocedurekillsthesecellswhichhavenewlyenteredthecellcycle.[10]

Thefastestcyclingmammaliancellsinculture,cryptcellsintheintestinalepithelium,haveacycletimeasshortas9to10hours.Stemcellsinrestingmouseskinmay
haveacycletimeofmorethan200hours.MostofthisdifferenceisduetothevaryinglengthofG1,themostvariablephaseofthecycle.MandSdonotvarymuch.
Ingeneral,cellsaremostradiosensitiveinlateMandG2phasesandmostresistantinlateSphase.
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ForcellswithalongercellcycletimeandasignificantlylongG1phase,thereisasecondpeakofresistancelateinG1.
Thepatternofresistanceandsensitivitycorrelateswiththelevelofsulfhydrylcompoundsinthecell.Sulfhydrylsarenaturalsubstancesthatprotectcellsfromradiation
damageandtendtobeattheirhighestlevelsinSandattheirlowestnearmitosis.

Seealso
Cellularmodel
Synchronousculturesynchronizationofcellcultures

References
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3.Rubenstein,Irwin,andSusanM.Wick."Cell."WorldBookOnlineReferenceCenter.
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4.Maton,Anthea(1997).Cells:BuildingBlocksofLife.NewJersey:PrenticeHall.
pp.704.ISBN0134234766.
5.DeSouzaCP,OsmaniSA(2007)."Mitosis,notjustopenorclosed".EukaryoticCell.
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6.LillyM,DuronioR(2005)."NewinsightsintocellcyclecontrolfromtheDrosophila
endocycle".Oncogene.24(17):276575.doi:10.1038/sj.onc.1208610.
PMID15838513.
7.NiggEA(June1995)."Cyclindependentproteinkinases:keyregulatorsofthe
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PMID7575488.
8."Pressrelease".Nobelprize.org.
9.SpellmanPT,SherlockG,ZhangMQ,IyerVR,AndersK,EisenMB,BrownPO,
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Furtherreading
MorganDO(2007).TheCellCycle:PrinciplesofControl.London:PublishedbyNew
SciencePressinassociationwithOxfordUniversityPress.ISBN0878935088.
AlbertsB,JohnsonA,LewisJ,RaffM,RobertsK,WalterP(2008)."Chapter17".
MolecularBiologyoftheCell(5thed.).NewYork:GarlandScience.ISBN9780
815341116.
KriegerM,ScottMP,MatsudairaPT,LodishHF,DarnellJE,ZipurskyL,KaiserC,
BerkA(2004).Molecularcellbiology.NewYork:W.H.FreemanandCO.ISBN0
716743663.
WatsonJD,BakerTA,BellSP,GannA,LevineM,LosickR(2004)."Chapter7".

WatsonJD,BakerTA,BellSP,GannA,LevineM,LosickR(2004)."Chapter7".
Molecularbiologyofthegene(5thed.).SanFrancisco:Pearson/BenjaminCummings.
ISBN0805346422.

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ThisarticleincorporatespublicdomainmaterialfromtheNCBIdocument"SciencePrimer"(http://www.ncbi.nlm.nih.gov/
About/primer/index.html).
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