2. Academic Validation
  3. The PRMT5-splicing axis is a critical oncogenic vulnerability that regulates detained intron splicing

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

  • bioRxiv. 2024 Dec 20:2024.12.17.628905. doi: 10.1101/2024.12.17.628905.
Colin E Fowler 1 2,  Natalie A O'Hearn 1 3,  Griffin J Salus 1 3,  Arundeep Singh 1,  Paul L Boutz 4 5,  Jacqueline A Lees 1 2
Affiliations

Affiliations

  • 1 The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 3 These authors contributed equally.
  • 4 Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, University of Rochester, Rochester, NY, 14642, USA.
  • 5 Center for RNA Biology, and Center for Biomedical Informatics, University of Rochester, Rochester, NY, 14642, USA.
PMID: 39763796 DOI: 10.1101/2024.12.17.628905
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.

Keywords

CLNS1A; PRMT5; detained introns; methylosome; splicing.

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