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

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.