InitiationofDNAreplicationineukaryotesisahighlyconserved,multi-stepprocess(replicationlicensing)designedtorestrictinitiationeventstoonceperreplicationoriginperSphase.Itscontrolhasbeenuncoveredbythediscoveryofthecyclindependentkinases(CDKs)asmasterregulatorsofthecellcycleandtheinitiatorproteinsofDNAreplication,suchastheOriginRecognitionComplex(ORC),Cdc6/18,Cdt1andthemini-chromosomemaintenancecomplex(Mcm).Theproteinsandthesequenceofeventsinvolvedinthisprocessareconservedthroughouttheeukaryotickingdom.First,theORCcomprisedofsixproteinsbindstoreplicationoriginsinthechromosomalDNA.Attheendofmitosis,ORC,Cdc6/18andCdt1assistthebindingofMcmproteins2–7tochromatin,andchromatinbecomeslicensedforreplication.TheactivatedMcmcomplexfunctionsasareplicatinghelicaseandmovesalongwiththereplicationforktobringtheoriginstotheunlicensedstate.ThecyclingofCDKactivityinthecellcycleregulatesthetwostatesofreplicationorigins,thelicensedstateinG1-phaseandtheunlicensedstatefortherestofthecellcycle.TherestrictiononlicensingisrelievedwhenCDKfallsoffatthecompletionofmitosistoallowanewroundofreplication.

Contributor:StefanGruenwald,MD,PhD

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