Inhighereukaryoticgenomes,LongInterspersedNuclearElement1(LINE-1)retrotransposonsrepresentalargefamilyofrepeatedgenomicelements.Theytransposeusingareversetranscriptase(RT),whichtheyencodeaspartoftheORF2pproduct.RTinhibitionincancercells,eitherviaRNAinterference-dependentsilencingofactiveLINE-1elements,orusingRTinhibitorydrugs,reducescancercellproliferation,promotestheirdifferentiationandantagonizestumorprogressioninanimalmodels.Indeed,thenon-nucleosideRTinhibitorefavirenzhasrecentlybeentestedinaphaseIIclinicaltrialwithmetastaticprostatecancerpatients.Anin-depthanalysisofORF2pinamousemodelofbreastcancershowedORF2ptobeprecociouslyexpressedinprecancerouslesionsandhighlyabundantinadvancedcancerstages,whilebeingbarelydetectableinnormalbreasttissue,providingarationaleforthefindingthatRT-expressingtumorsaretherapeuticallysensitivetoRTinhibitors.WesummarizemechanisticandgeneprofilingstudiesindicatingthatabundantLINE-1-derivedRTcan"sequester"RNAsubstratesforreversetranscriptionintumorcells,entailingtheformationofRNA:DNAhybridmoleculesandimpairingtheoverallproductionofregulatorymiRNAs,withaglobalimpactonthecelltranscriptome.Basedonthesedata,LINE-1-ORF2encodedRThasatumor-promotingpotentialthatisexertedatanepigeneticlevel.WeproposeamodelwherebyLINE1-RTdrivesapreviouslyunrecognizedglobalregulatoryprocess,thederegulationofwhichdrivescelltransformationandtumorigenesiswithpossibleimplicationsforcancercell heterogeneity.
The reverse transcriptase encoded by LINE-1 retrotransposons in the genesis, progression and therapy of cancer
Corrado Spadafora
2016
Abstract
Inhighereukaryoticgenomes,LongInterspersedNuclearElement1(LINE-1)retrotransposonsrepresentalargefamilyofrepeatedgenomicelements.Theytransposeusingareversetranscriptase(RT),whichtheyencodeaspartoftheORF2pproduct.RTinhibitionincancercells,eitherviaRNAinterference-dependentsilencingofactiveLINE-1elements,orusingRTinhibitorydrugs,reducescancercellproliferation,promotestheirdifferentiationandantagonizestumorprogressioninanimalmodels.Indeed,thenon-nucleosideRTinhibitorefavirenzhasrecentlybeentestedinaphaseIIclinicaltrialwithmetastaticprostatecancerpatients.Anin-depthanalysisofORF2pinamousemodelofbreastcancershowedORF2ptobeprecociouslyexpressedinprecancerouslesionsandhighlyabundantinadvancedcancerstages,whilebeingbarelydetectableinnormalbreasttissue,providingarationaleforthefindingthatRT-expressingtumorsaretherapeuticallysensitivetoRTinhibitors.WesummarizemechanisticandgeneprofilingstudiesindicatingthatabundantLINE-1-derivedRTcan"sequester"RNAsubstratesforreversetranscriptionintumorcells,entailingtheformationofRNA:DNAhybridmoleculesandimpairingtheoverallproductionofregulatorymiRNAs,withaglobalimpactonthecelltranscriptome.Basedonthesedata,LINE-1-ORF2encodedRThasatumor-promotingpotentialthatisexertedatanepigeneticlevel.WeproposeamodelwherebyLINE1-RTdrivesapreviouslyunrecognizedglobalregulatoryprocess,thederegulationofwhichdrivescelltransformationandtumorigenesiswithpossibleimplicationsforcancercell heterogeneity.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
