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U2AF1 mutation connects DNA damage to the alternative splicing of RAD51 in lung adenocarcinomas

Chuanhui Chen1, Pinglang Zhou1, Zhizhe Zhang1

  • 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Clinical and Experimental Pharmacology & Physiology
|April 18, 2022
PubMed

Insights

The U2AF1-S34F mutation in lung cancer disrupts DNA repair factor splicing, increasing DNA damage and cell death. This mutation sensitizes cancer cells to RAD51 inhibition, offering a potential therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cancer Genetics
  • RNA Splicing

Background:

  • The U2AF1 S34F mutation is common in lung adenocarcinoma.
  • The functional impact of this mutation is poorly understood.

Purpose of the Study:

  • To investigate the mechanistic basis and consequences of U2AF1 mutations in lung cancer.
  • To determine how U2AF1-S34F affects DNA damage repair and drug sensitivity.

Main Methods:

  • Established A549 cell lines expressing wildtype (U2AF1-WT) or mutant (U2AF1-S34F) U2AF1.
  • Conducted splicing analysis to identify affected genes.
  • Assessed DNA damage and cell death in response to ATR inhibitors (ATRi).

Main Results:

  • U2AF1-S34F caused aberrant exon usage and affected splicing of DNA damage repair genes.
  • Cells with U2AF1-S34F exhibited increased DNA damage and cell death upon ATRi treatment.
  • U2AF1-S34F led to RAD51 mis-splicing and downregulation, which could be rescued by RAD51 overexpression.
  • U2AF1-S34F expressing cells showed heightened sensitivity to RAD51 inhibition combined with ATRi.

Conclusions:

  • U2AF1-S34F mutation induces mis-splicing of DNA damage repair factors in lung cancer.
  • This mis-splicing sensitizes lung cancer cells to RAD51 inhibition, particularly in the context of ATR inhibitor treatment.
Keywords:
DNA damageRAD51U2AF1lung cancer

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