U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Mechanisms linking U2AF1 mutations to lung adenocarcinoma pathogenesis remain unclear.
• Oncogenic mutations in KRAS are common drivers in lung cancer.
• Alternative splicing dysregulation is a hallmark of cancer.

Purpose of the Study:

• To investigate how U2AF1 mutations impact alternative splicing in lung adenocarcinoma.
• To explore the functional consequences of splicing factor-oncogene mutation co-occurrence.
• To elucidate the role of splicing factor mutations in rescuing oncogenic splicing defects.

Main Methods:

• Utilized prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells.
• Assessed the impact of U2AF1 mutations on alternative splicing patterns.
• Analyzed co-occurrence of splicing factor and oncogene mutations in cancer genomes.
• Experimentally validated the rescue of KRAS splicing defects by U2AF1 mutants.

Main Results:

• A KRAS G12S mutation caused exon 2 skipping, generating a nonfunctional transcript.
• U2AF1 S34F mutant expression restored KRAS function by reverting exon skipping, correlating with U2AF1 S34F enrichment in KRAS G12S tumors.
• KRAS Q61R mutation induced exon 3 skipping, which was rescued by U2AF1 I24T expression.
• Significant co-enrichment of KRAS Q61R and U2AF1 I24T mutations was observed.

Conclusions:

• Splicing factor mutations can functionally rescue splicing defects induced by oncogenic mutations.
• This rescue mechanism represents a dynamic process of cascading selection in cancer evolution.
• Findings provide novel insights into the interplay between splicing factors and oncogenes in lung adenocarcinoma development.