The University of Southampton
University of Southampton Institutional Repository

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

Text
NAT-2016-0635-Kralovicova_1P.pdf - Accepted Manuscript
Download (471kB)

More information

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

Catalogue record

Date deposited: 30 Sep 2016 12:26
Last modified: 07 Oct 2020 06:23

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×