U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations
摘要
The mechanisms by which mutations of splicing factor gene U2AF1 contribute to lung adenocarcinoma pathogenesis are not well understood. Here we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the impact on alternative splicing. One specific KRAS mutation, G12S, led to skipping of KRAS exon 2 and generation of a nonfunctional KRAS transcript. However, expression of the U2AF1S34F mutant reverted this exon skipping and restored KRAS function, leading to enrichment of U2AF1S34F mutations in KRASG12S-mutant lung adenocarcinomas. Comprehensive analysis of splicing factor–oncogene mutation co-occurrence in cancer genomes also revealed significant coenrichment of KRASQ61R and U2AF1I24T mutations. Experimentally, KRASQ61R mutation led to KRAS exon 3 skipping, which in turn could be rescued by expression of U2AF1I24T. Our findings provide evidence that splicing factor mutations can rescue splicing defects caused by oncogenic mutations in a dynamic process of cascading selection.