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We show that a key <jats:underline>n<\/jats:underline>onsense-mediated RNA decay <jats:underline>s<\/jats:underline>witch <jats:underline>e<\/jats:underline>xon (NSE) in <jats:italic>ATM<\/jats:italic> is repressed by U2AF, PUF60 and hnRNPA1. The NSE activation was haplotype-specific and was most promoted by cytosine at rs609261 in the NSE 3\u2032 splice-site (3\u2032ss), 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 <jats:underline>s<\/jats:underline>plice-<jats:underline>s<\/jats:underline>witching <jats:underline>o<\/jats:underline>ligonucleotides (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. 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