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The transcription factor c-Jun inhibits RBM39 to reprogram pre-mRNA splicing during genotoxic stress

Florence Lemaitre1, Fatima Chakrama2, Tina O'Grady1

  • 1Laboratory of Gene Expression and Cancer, GIGA-Molecular Biology of Diseases, B34, University of Liège, Liège 4000, Belgium.

Nucleic Acids Research
|December 8, 2022
PubMed

Insights

Cisplatin treatment in breast cancer cells alters gene splicing, affecting mitochondrial function and drug resistance. A novel interaction between splicing regulator RBM39 and transcription factor c-Jun was discovered, impacting gene expression and cancer cell survival.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Genotoxic cancer therapies like cisplatin reprogram cancer cell transcriptomes.
  • These transcriptomic changes are linked to cellular stress responses and drug resistance mechanisms.

Purpose of the Study:

  • To investigate genome-wide pre-mRNA splicing alterations induced by cisplatin in breast cancer cells.
  • To identify key regulators and mechanisms underlying cisplatin-induced splicing changes and their role in drug resistance.

Main Methods:

  • Genome-wide profiling of pre-mRNA splicing changes induced by cisplatin.
  • Focus on the COASY gene and its isoforms.
  • Identification and characterization of splicing factor RBM39 and its interaction partners.

Main Results:

  • Cisplatin treatment induces a specific short isoform of COASY, impairing mitochondrial function and reducing cisplatin sensitivity.
  • RBM39 is identified as a key regulator of cisplatin-induced COASY splicing and controls a broader set of alternative splicing events.
  • RBM39 inactivation by cisplatin involves an interaction with c-Jun, preventing RBM39 binding to pre-mRNA.

Conclusions:

  • A novel cisplatin-induced interaction between splicing regulator RBM39 and transcription factor c-Jun globally impacts alternative splicing.
  • This RBM39-c-Jun interaction contributes to cisplatin resistance in breast cancer cells.
  • Understanding this mechanism offers potential therapeutic strategies for overcoming drug resistance.

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