The PRMT5-splicing axis is a critical oncogenic vulnerability that regulates detained intron splicing

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Protein arginine methyltransferase 5 (PRMT5) is a key target in cancer therapy.
• The precise mechanisms by which PRMT5 inhibition affects cancer cell viability remain incompletely understood.

Purpose of the Study:

• To elucidate the functional roles of PRMT5 in cancer cell vulnerability.
• To investigate the connection between PRMT5, splicing, and cell survival.

Main Methods:

• Utilized PRMT5 inhibition and depletion of its cofactor CLNS1A.
• Analyzed the induction of detained introns (DIs) and Sm protein methylation.
• Performed comparative analysis of DI conservation across human and mouse cell lines.

Main Results:

• PRMT5 inhibition specifically induces a class of unspliced introns known as detained introns (DIs).
• Loss of CLNS1A-mediated Sm protein methylation leads to DI upregulation and reduced cell viability in sensitive cell lines.
• PRMT5-regulated DIs and affected genes show high conservation between human and mouse cells, impacting proliferation pathways.

Conclusions:

• The PRMT5-splicing axis, characterized by the regulation of DI splicing, is critical for cancer cell sensitivity to PRMT5 inhibitors.
• Targeting PRMT5 impacts splicing through DI induction, offering a novel therapeutic vulnerability in cancer.