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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, Griffin J Salus1
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 is unclear which PRMT5 roles underlie this vulnerability. Here, we establish that PRMT5 inhibition induces a special class of unspliced introns, called detained introns (DIs). We used the depletion of CLNS1A, a PRMT5 cofactor that specifically enables Sm protein methylation, to interrogate the impact of DIs. We found that the disruption of Sm protein methylation is sufficient to induce DI upregulation, cell cycle defects, and loss of viability. 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, and particularly appropriate DI splicing, underlie cancer's vulnerability to PRMT5 inhibitors.
Insights
Targeting Protein arginine methyltransferase 5 (PRMT5) in cancer is promising. PRMT5 inhibition causes detained introns (DIs), leading to cell cycle defects and reduced viability, revealing a key vulnerability.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- Protein arginine methyltransferase 5 (PRMT5) is a validated cancer target.
- The specific mechanisms by which PRMT5 inhibition impacts cancer cells remain incompletely understood.
Purpose of the Study:
- To elucidate the functional role of PRMT5 in cancer cell vulnerability.
- To investigate the link between PRMT5 activity, RNA splicing, and cancer progression.
Main Methods:
- Depletion of the PRMT5 cofactor CLNS1A to disrupt Sm protein methylation.
- Analysis of detained intron (DI) accumulation and its downstream effects.
- Comparative analysis of DI conservation and function in human and mouse cell lines.
Main Results:
- PRMT5 inhibition specifically induces the accumulation of detained introns (DIs).
- Disruption of Sm protein methylation by CLNS1A depletion is sufficient to cause DI upregulation, cell cycle arrest, and decreased cell viability.
- PRMT5-regulated DIs and affected genes show high conservation between human and mouse cells, impacting proliferation pathways convergently.
Conclusions:
- The PRMT5-splicing axis, particularly the regulation of DI splicing, represents a critical vulnerability in cancer.
- PRMT5 inhibitors exploit this axis, leading to detrimental effects on cancer cell proliferation and survival.
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