SRSF2 Regulation of MDM2 Reveals Splicing as a Therapeutic Vulnerability of the p53 Pathway

Area of Science:

• Molecular Biology
• Cancer Biology
• RNA Splicing

Background:

• MDM2 is an oncogene that negatively regulates tumor suppressor p53.
• Genotoxic stress induces alternative splicing of MDM2 transcripts, affecting p53 activity and promoting tumorigenesis.
• MDM2-ALT1, an alternatively spliced MDM2 transcript, is increased by genotoxic stress.

Purpose of the Study:

• To investigate the role of splicing regulator SRSF2 in MDM2 alternative splicing.
• To understand how SRSF2 influences the generation of MDM2-ALT1.
• To explore the therapeutic potential of modulating MDM2 splicing.

Main Methods:

• Investigated SRSF2's interaction with MDM2 exon 11.
• Utilized SRSF2 overexpression and knockdown experiments.
• Employed oligonucleotide-based blocking of SRSF2-binding sites.
• Generated CRISPR-Cas9 Mdm2 exon 11 mutants in mice.

Main Results:

• SRSF2 antagonizes SRSF1-mediated MDM2-ALT1 generation by promoting exon 11 inclusion.
• SRSF2 overexpression decreases MDM2-ALT1 under genotoxic stress; SRSF2 knockdown increases it.
• Blocking SRSF2-binding sites enhances MDM2-ALT1 splicing, p53 expression, and apoptosis.
• SRSF2 regulation of MDM2 splicing is conserved in mice, with mutations increasing Mdm2-MS2 expression.

Conclusions:

• SRSF2 acts as a key regulator of MDM2 alternative splicing, opposing SRSF1.
• Modulating MDM2 splicing via SRSF2 offers a potential strategy for controlling p53 activity in cancer.
• Targeting MDM2 splicing may represent a novel therapeutic approach for genotoxic stress-induced tumorigenesis.