U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.

Authors

David M Walter, Katherine Cho, Smruthy Sivakumar, Daniel Denney, Iris T Lee, Anders B Dohlman, Jakob M Heinz, Ethan Shurberg, Kevin X Jiang, Akansha A Gupta, Garrett M Frampton, Matthew Meyerson

Published in

Nature genetics. Jul 01, 2026. Epub Jul 01, 2026.

Abstract

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 U2AF1^S34F mutant reverted this exon skipping and restored KRAS function, leading to enrichment of U2AF1^S34F mutations in KRAS^G12S-mutant lung adenocarcinomas. Comprehensive analysis of splicing factor-oncogene mutation co-occurrence in cancer genomes also revealed significant coenrichment of KRAS^Q61R and U2AF1^I24T mutations. Experimentally, KRAS^Q61R mutation led to KRAS exon 3 skipping, which in turn could be rescued by expression of U2AF1^I24T. Our findings provide evidence that splicing factor mutations can rescue splicing defects caused by oncogenic mutations in a dynamic process of cascading selection.

PMID:
42386932
Bibliographic data and abstract were imported from PubMed on 02 Jul 2026.

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