RPL22 is a tumor suppressor in MSI-high cancers and a key splicing regulator of MDM4

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Microsatellite instability high (MSI-H) tumors are characterized by a high mutational burden but often retain wild-type TP53.
• Frameshift mutations in RPL22, a ribosomal protein, are frequently observed in MSI-H tumors.
• Understanding the molecular mechanisms driving MSI-H tumorigenesis is crucial for developing targeted therapies.

Approach:

• Investigated the role of RPL22 in modulating MDM4 splicing using alternative splicing analysis.
• Examined the functional consequences of RPL22 loss on cell proliferation and drug resistance.
• Assessed the impact of RPL22 on the expression of its paralog, RPL22L1, through splicing assays.

Key Points:

• Identified RPL22 as a regulator of MDM4 alternative splicing, specifically controlling exon 6 inclusion.
• Demonstrated that RPL22 loss leads to increased MDM4 exon 6 inclusion, promoting cell proliferation and resistance to MDM inhibitors.
• Revealed that RPL22 represses RPL22L1 expression by splicing a cryptic exon, leading to truncated transcripts.

Conclusions:

• Damaging mutations in RPL22 can drive oncogenic MDM4 induction and RPL22L1 upregulation in MSI-H tumors.
• A common splicing circuit involving RPL22, MDM4, and RPL22L1 is implicated in MSI-H tumorigenesis.
• This splicing circuit represents a potential therapeutic target for MSI-H cancers, particularly concerning the MDM4-p53 axis.