Nucleotide Deficiency Promotes Genomic Instability in Early Stages of Cancer Development

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1、NucleotideDeficiencyPromotesGenomicInstabilityinEarlyStagesofCancerDevelopmentAssafC.Bester,1MaayanRoniger,1YifatS.Oren,1MichaelM.Im,3DanSarni,1MalkaChaoat,2AaronBensimon,4GideonZamir,2DonnaS.Shewach,3andBatshevaKerem1,*1DepartmentofGenetics,TheLifeSciencesInstit

2、ute,EdmondJ.SafraCampus2DepartmentofSurgery,HadassahMedicalSchoolTheHebrewUniversity,Jerusalem91905,Israel3DepartmentofPharmacology,UniversityofMichiganMedicalCenter,AnnArbor,MI48109,USA4GenomicVision,29rueFaubourgSaintJacques,75014Paris,France*Correspondence:ke

3、rem@cc.huji.ac.ilDOI10.1016/j.cell.2011.03.044SUMMARYAnotheroncogenethataberrantlyactivatestheRb-E2FpathwayiscyclinE,whichisoverexpressedinmanycancers,Chromosomalinstabilityinearlycancerstagesisincludingcarcinomas,lymphomas,leukemias,andsarcomascausedbystressonD

4、NAreplication.Themolecular(AkliandKeyomarsi,2003).CyclinEregulatesSphaseentrybasisforreplicationperturbationinthiscontextisbyRbphosphorylationandinactivation,facilitatingE2Frelease.currentlyunknown.WestudiedthereplicationOverexpressionofcyclinEgreatlyaccelerates

5、SphaseentryindynamicsincellsinwhicharegulatorofSphaseculturedcells(OhtsuboandRoberts,1993).AberrantactivationoftheRb-E2Fpathwayleadstotheforma-entryandcellproliferation,theRb-E2Fpathway,istionofDNAdouble-strandbreaks(DSBs)andchromosomalaberrantlyactivated.Aberra

6、ntactivationofthisinstability(Frameetal.,2006;PickeringandKowalik,2006).pathwaybyHPV-16E6/E7orcyclinEoncogenesThisleadstosenescenceorapoptosis,providingabarriertosignificantlydecreasedthecellularnucleotidelevelscancerprogression.Inordertoovercomethisbarrier,thehi

7、gh-inthenewlytransformedcells.ExogenouslysuppliedriskHPVexpressestheE6oncoprotein,whichinducesprotea-nucleosidesrescuedthereplicationstressandDNAsomaldegradationofp53,thusavoidingcell-cyclearrestordamageanddramaticallydecreasedoncogene-apoptosis.Hence,together,E

8、6andE7enableproliferativeinducedtransformation.IncreasedtranscriptionofactivityofHPV-infectedcells(DuensingandMu¨nger,2004).Innucleotidebiosynthesisgenes,mediatedbyex