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The PRMT5-splicing axis is a critical oncogenic vulnerability that regulates detained intron splicing
Colin E Fowler1,2, Natalie A O'Hearn1,3, Griffin J Salus1,3
1The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
Protein arginine methyltransferase 5 (PRMT5) is a promising cancer target, yet it's unclear which PRMT5 roles underlie this vulnerability. Here, we establish that PRMT5 inhibition induces a special class of unspliced introns, called detained introns (DIs). To interrogate the impact of DIs, we depleted CLNS1A, a PRMT5 cofactor that specifically enables Sm protein methylation. We found that many, but not all, cell lines are CLNS1A-dependent and established that loss of viability is linked to loss of Sm protein methylation and DI upregulation. Finally, we discovered that PRMT5-regulated DIs, and the impacted genes, are highly conserved across human, and also mouse, cell lines but display little interspecies conservation. Despite this, human and mouse DIs have convergent impacts on proliferation by affecting essential components of proliferation-regulating complexes. Together, these data argue that the PRMT5-splicing axis, including appropriate DI splicing, underlies cancer's vulnerability to PRMT5 inhibitors.
Insights
Protein arginine methyltransferase 5 (PRMT5) inhibition causes detained introns (DIs). This PRMT5-splicing axis, including DI splicing, reveals cancer
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.
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