G4-DNA Formation in the HRAS Promoter and Rational Design of Decoy Oligonucleotides for Cancer Therapy 英文参考文献.docVIP

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G4-DNA Formation in the HRAS Promoter and Rational Design of Decoy Oligonucleotides for Cancer Therapy 英文参考文献.doc

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G4-DNA Formation in the HRAS Promoter and Rational Design of Decoy Oligonucleotides for Cancer Therapy 英文参考文献

G4-DNAFormationintheHRASPromoterandRational DesignofDecoyOligonucleotidesforCancerTherapy AlexandroMembrino1,SusannaCogoi1,ErikB.Pedersen2,LuigiE.Xodo1* 1Department of Medical and Biological Science, School of Medicine, Udine, Italy, 2Nucleic Acid Center, Institute of Physics and Chemistry, University of Southern Denmark,Odense,Denmark Abstract HRASisaproto-oncogeneinvolvedinthetumorigenesisofurinarybladdercancer.IntheHRASpromoterweidentifiedtwo G-richelements,hras-1andhras-2,thatfold,respectively,intoanantiparallelandaparallelquadruplex(qhras-1,qhras-2). When we introduced in sequence hras-1 or hras-2 two point mutations that block quadruplex formation, transcription increased5-fold,butwhenwestabilizedtheG-quadruplexesbyguanidiniumphthalocyanines,transcriptiondecreasedto 20%ofcontrol.ByChIPwefoundthatsequencehras-1isboundonlybyMAZ,whilehras-2isboundbyMAZandSp1:two transcription factors recognizing guanine boxes. We also discovered by EMSA that recombinant MAZ-GST binds toboth HRASquadruplexes,whileSp1-GSTonlybindstoqhras-1.Theover-expressionofMAZandSp1synergisticallyactivatesHRAS transcription,whilesilencingeachgenebyRNAiresultsinastrongdown-regulationoftranscription.Allthesedataindicate thattheHRASG-quadruplexesbehaveastranscriptionrepressors.Finally,wedesigneddecoyoligonucleotidesmimicking the HRAS quadruplexes, bearing (R)-1-O-[4-(1-Pyrenylethynyl) phenylmethyl] glycerol and LNA modifications to increase their stability and nuclease resistance (G4-decoys). The G4-decoys repressed HRAS transcription and caused a strong antiproliferativeeffect,mediatedbyapoptosis,inT24bladdercancercellswhereHRASismutated. Citation:MembrinoA,CogoiS,PedersenEB,XodoLE(2011)G4-DNAFormationintheHRASPromoterandRationalDesignofDecoyOligonucleotidesforCancer Therapy.PLoSONE6(9):e24421.doi:10.1371/journal.pone.0024421 Editor:MarkIsalan,CenterforGenomicRegulation,Spain ReceivedJune3,2011;AcceptedAugust9,2011;PublishedSeptember8,2011 Copyright: ?2011 Membrino et al. This is an open-access