TheinitiationofDNAreplicationinmammaliancellsisahighlycoordinatedprocessthatensuresduplicationofthegenomeonlyoncepercelldivisioncycle.Originsofreplicationaredispersedthroughoutthegenomeandtheiractivitiesareregulatedviathesequentialbindingofpre-replicationandreplicationfactors.Theoriginrecognitioncomplex(ORC)isthoughttobindtochromatinthroughoutthecellcycle(1,2).Thepre-replicationcomplex(Pre-RC)formsinlatemitosis/earlyG1phasewiththebindingofCDT1andcdc6totheorigin,whichallowsbindingoftheheterohexamericMCM2-7complex.TheMCMcomplexisthoughttobethereplicativehelicaseandformationofthepre-RCisreferredtoaschromatinlicensing.SubsequentinitiationofDNAreplicationrequirestheactivationoftheS-phasepromotingkinasescdk2andcdc7.Cdc7phosphorylatesMCMproteinsboundtochromatinand,inconjunctionwithCDT1,recruitsthereplicationfactorcdc45(3-5).Cdc45isrequiredforformationofpre-initiationcomplexesattheG1/Stransitionandforactivationofreplicationorigins.Thelevelofcdc45proteinexpressionisassociatedwiththeproliferativestatusofthecellortissue.Terminallydifferentiatedandsenescentcellslackcdc45andhighlyproliferativecelllinesexpresshighlevelsofcdc45(6).
