U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations

Here, we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the resulting impact on alternative splicing. One specific KRAS mutation, G12S, leads to skipping of KRAS exon 2 and generation of a non-functional KRAS transcript.

However, expression of the U2AF1 S34F mutant reverts this exon skipping and restores KRAS function, leading to an enrichment of U2AF1 S34F mutations in KRAS G12S-mutant lung adenocarcinomas. A comprehensive analysis of splicing factor/oncogene mutation co-occurrence in cancer genomes also revealed significant co-enrichment of KRAS Q61R and U2AF1 I24T mutations. Experimentally, KRAS Q61R mutation leads to KRAS exon 3 skipping, which in turn can be rescued by the expression of U2AF1 I24T.