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Exon-centric regulation of ATM expression is population-dependent and amenable to antisense modification by pseudoexon targeting

Exon-centric regulation of ATM expression is population-dependent and amenable to antisense modification by pseudoexon targeting
Exon-centric regulation of ATM expression is population-dependent and amenable to antisense modification by pseudoexon targeting
ATM is an important cancer susceptibility gene that encodes a critical apical kinase of the DNA damage response (DDR) pathway. We show that a key nonsense-mediated RNA decay switch exon (NSE) in ATM is repressed by U2AF, PUF60 and hnRNPA1. The NSE activation was haplotype-specific and was most promoted by cytosine at rs609621 in the NSE 3? splice-site (3?ss), which is predominant in high cancer risk populations. NSE levels were deregulated in leukemias and were influenced by the identity of U2AF35 residue 34. We also identify splice-switching oligonucleotides (SSOs) that exploit competition of adjacent pseudoexons to modulate NSE levels. The U2AF-regulated exon usage in the ATM signalling pathway was centred on the MRN/ATM-CHEK2-CDC25-cdc2/cyclin-B axis and preferentially involved transcripts implicated in cancer-associated gene fusions and chromosomal translocations. These results reveal important links between 3?ss control and ATM-dependent responses to double-strand DNA breaks, demonstrate functional plasticity of intronic variants and illustrate versatility of intronic SSOs that target pseudo-3?ss to modify gene expression.
1-13
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Knut, Marcin
68d387d0-9b44-48d1-91c6-310f7470cdc2
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Knut, Marcin
68d387d0-9b44-48d1-91c6-310f7470cdc2
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e

Kralovicova, Jana, Knut, Marcin, Cross, Nicholas C.P. and Vorechovsky, Igor (2016) Exon-centric regulation of ATM expression is population-dependent and amenable to antisense modification by pseudoexon targeting. Scientific Reports, 6 (18741), 1-13. (doi:10.1038/srep18741). (PMID:26732650)

Record type: Article

Abstract

ATM is an important cancer susceptibility gene that encodes a critical apical kinase of the DNA damage response (DDR) pathway. We show that a key nonsense-mediated RNA decay switch exon (NSE) in ATM is repressed by U2AF, PUF60 and hnRNPA1. The NSE activation was haplotype-specific and was most promoted by cytosine at rs609621 in the NSE 3? splice-site (3?ss), which is predominant in high cancer risk populations. NSE levels were deregulated in leukemias and were influenced by the identity of U2AF35 residue 34. We also identify splice-switching oligonucleotides (SSOs) that exploit competition of adjacent pseudoexons to modulate NSE levels. The U2AF-regulated exon usage in the ATM signalling pathway was centred on the MRN/ATM-CHEK2-CDC25-cdc2/cyclin-B axis and preferentially involved transcripts implicated in cancer-associated gene fusions and chromosomal translocations. These results reveal important links between 3?ss control and ATM-dependent responses to double-strand DNA breaks, demonstrate functional plasticity of intronic variants and illustrate versatility of intronic SSOs that target pseudo-3?ss to modify gene expression.

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Accepted/In Press date: 25 November 2015
e-pub ahead of print date: 6 January 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 385660
URI: http://eprints.soton.ac.uk/id/eprint/385660
PURE UUID: d15a67ca-1838-491b-a045-7f54a4a8ebf3
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 21 Jan 2016 09:26
Last modified: 26 Nov 2019 01:51

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