title: Exon-centric regulation of ATM expression is population-dependent and amenable to antisense modification by pseudoexon targeting.
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.
authors.affiliation: University of Southampton Faculty of Medicine Southampton SO16 6YD United Kingdom.
authors.forename: Jana
authors.initials: J
authors.lastname: Kralovicova
authors.affiliation: University of Southampton Faculty of Medicine Southampton SO16 6YD United Kingdom.
authors.forename: Marcin
authors.initials: M
authors.lastname: Knut
authors.affiliation: University of Southampton Faculty of Medicine Southampton SO16 6YD United Kingdom.|Wessex Regional Genetics Laboratory Salisbury Hospital Salisbury SP2 8BJ United Kingdom.
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.affiliation: University of Southampton Faculty of Medicine Southampton SO16 6YD United Kingdom.
authors.forename: Igor
authors.initials: I
authors.lastname: Vorechovsky
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D016373:DNA, Antisense / Q000235:genetics*; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011544:Pseudogenes; D012323:RNA Processing, Post-Transcriptional; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D000072668:Splicing Factor U2AF / Q000378:metabolism
chemical_list: D016373:DNA, Antisense; D009841:Oligonucleotides; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D000072668:Splicing Factor U2AF; D064007:Ataxia Telangiectasia Mutated Proteins