Nature geneticsJul 1, 2026

U2AF1 mutations may reverse harmful gene skipping caused by KRAS mutations

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 2, 2026

Abstract

Mutations in the U2AF1 gene can reverse splicing defects caused by specific KRAS mutations in lung adenocarcinoma.

A KRAS mutation (G12S) resulted in skipping of KRAS exon 2, creating a nonfunctional transcript.
Expression of the U2AF1^S34F mutant restored KRAS function by preventing exon skipping.
U2AF1^S34F mutations were enriched in lung adenocarcinomas with KRAS^G12S mutations.
Analysis showed significant coenrichment of KRAS^Q61R and U2AF1^I24T mutations in cancer genomes.
KRAS^Q61R mutation caused skipping of KRAS exon 3, which could be rescued by U2AF1^I24T expression.

Simplified

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.