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dc.creatorKralovicova, J
dc.creatorMoreno, PM
dc.creatorCross, N
dc.creatorPêgo, AP
dc.creatorVorechovsky, I
dc.description.abstractATM (ataxia-telangiectasia, mutated) is an important cancer susceptibility gene that encodes a key apical kin ase in the DNA damage response pathway. ATM mutations in the germ line result in ataxia-telangiectasia (A-T), a rare genetic syndrome associated with hypersensitivity to double-strand DNA breaks and predisposition to lymphoid malignancies. ATM expression is limited by a tightly regulated nonsense-mediated RNA decay (NMD) switch exon (termed NSE) located in intron 28. In this study, we identify antisense oligonucleotides that modulate NSE inclusion in mature transcripts by systematically targeting the entire 3.1-kb-long intron. Their identification was assisted by a segmental deletion analysis of transposed elements, revealing NSE repression upon removal of a distant antisense Alu and NSE activation upon elimination of a long terminal repeat transposon MER51A. Efficient NSE repression was achieved by delivering optimized splice-switching oligonucleotides to embryonic and lymphoblastoid cells using chitosan-based nanoparticles. Together, these results provide a basis for possible sequence-specific radiosensitization of cancer cells, highlight the power of intronic antisense oligonucleotides to modify gene expression, and demonstrate transposon-mediated regulation of NSEs.
dc.description.sponsorshipThe authors wish to thank Professor Steven Marsh (UCL and the Anthony Nolan Trust) for a generous gift of the VAVY cell line. This work was funded by Bloodwise (grant 12060 to I.V. and N.C.P.C), Santa Casa da Misericordia de Lisboa—Premio Melo e Castro (grant MC-1068-2015 to A.P.P.), and Fundacão para a Ciência e Tecnologia (grant SFRH/BPD/108738/2015 to P.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.publisherMary Ann Liebert
dc.relation.ispartofNucleic Acid Therapeutics, vol. 26(6), p. 392-400
dc.subjectalternative splicing
dc.subjectantisense oligonucleotides
dc.subjectlymphoid cancer
dc.subjectnonsense-mediated RNA decay
dc.titleAntisense Oligonucleotides Modulating Activation of a Nonsense-Mediated RNA Decay Switch Exon in the ATM Gene
dc.typeArtigo em Revista Científica Internacional
dc.contributor.uportoInstituto de Investigação e Inovação em Saúde
Appears in Collections:I3S - Artigo em Revista Científica Internacional

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