U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.

ABSTRACT: The mechanisms by which somatic mutations of splicing factors, such as U2AF1^S34F in lung adenocarcinoma, contribute to cancer pathogenesis are not well understood. Here, we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the resulting impact on alternative splicing. These analyses identified KRAS as a key target modulated by U2AF1^S34F. One specific KRAS mutation, G12S, generates a cryptic U2AF1 binding site that leads to skipping of KRAS exon 2 and generation of a non-functional KRAS transcript. Expression of the U2AF1^S34F mutant reverts this exon skipping and restores KRAS function. Analysis of cancer genomes reveals that U2AF1^S34F mutations are enriched in KRAS<

SUBMITTER: Walter DM 

PROVIDER: S-EPMC11974705 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature