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Antisense oligonucleotides modulating activation of a nonsense-mediated mRNA decay switch exon in the ATM gene

Antisense oligonucleotides modulating activation of a nonsense-mediated mRNA decay switch exon in the ATM gene
Antisense oligonucleotides modulating activation of a nonsense-mediated mRNA decay switch exon in the ATM gene
ATM (ataxia-telangiectasia, mutated) is an important cancer susceptibility gene that encodes a key apical kinase 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
2159-3345
392-400
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Moreno, Pedro M.D.
52dc254e-fd18-4add-bf5a-a566bf3f94ad
Cross, Nicholas
f87650da-b908-4a34-b31b-d62c5f186fe4
Pego, Ana Paula
3a392ff5-fdb1-440f-9c6c-51ba2c336934
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Moreno, Pedro M.D.
52dc254e-fd18-4add-bf5a-a566bf3f94ad
Cross, Nicholas
f87650da-b908-4a34-b31b-d62c5f186fe4
Pego, Ana Paula
3a392ff5-fdb1-440f-9c6c-51ba2c336934
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e

Kralovicova, Jana, Moreno, Pedro M.D., Cross, Nicholas, Pego, Ana Paula and Vorechovsky, Igor (2016) Antisense oligonucleotides modulating activation of a nonsense-mediated mRNA decay switch exon in the ATM gene. Nucleic Acid Therapeutics, 26 (6), 392-400. (doi:10.1089/nat.2016.0635).

Record type: Article

Abstract

ATM (ataxia-telangiectasia, mutated) is an important cancer susceptibility gene that encodes a key apical kinase 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

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NAT-2016-0635-Kralovicova_1P.pdf - Accepted Manuscript
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Accepted/In Press date: 25 August 2016
Published date: December 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 400954
URI: http://eprints.soton.ac.uk/id/eprint/400954
ISSN: 2159-3345
PURE UUID: f1f238f8-68b9-44b4-a08c-7fa64ab6e5ae
ORCID for Nicholas Cross: ORCID iD orcid.org/0000-0001-5481-2555
ORCID for Igor Vorechovsky: ORCID iD orcid.org/0000-0002-6740-6502

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Date deposited: 30 Sep 2016 12:26
Last modified: 15 Mar 2024 05:56

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Contributors

Author: Jana Kralovicova
Author: Pedro M.D. Moreno
Author: Nicholas Cross ORCID iD
Author: Ana Paula Pego

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