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Cited by 3Cancer-related gene regulationRNA Research and SplicingRNA modifications and cancer

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

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Fowler, Colin E., O’Hearn, Natalie A., Salus, Griffin J., Singh, Arundeep, Boutz, Paul L., Lees, Jacqueline A.·2025·iScience
DOI 10.1016/j.isci.2025.112965PMC PMC12275038

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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.

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Metadata

Authors
Fowler, C. E., O’Hearn, N. A., Salus, G. J., Singh, A., Boutz, P. L., & Lees, J. A.
Affiliations
  • Koch Institute for Integrative Cancer Research At MIT (US)
  • University of Rochester Medicine (US)
Corresponding author
Lees, Jacqueline A.
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2025-07
Volume
28
Issue
7
Pages
112965
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2025.112965
PMC
PMC12275038
OpenAlex
W4411476613
Cited by
3
References
3
Citations by year
2026: 3
FWCI
0.90
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Massachusetts Institute of Technology Koch Institute for Integrative Cancer Research
  • NIH National Institute of General Medical Sciences (5T32GM136540)
  • National Institutes of Health National Cancer Institute (P30-CA014051, NCI-5P01CA042063-35)
  • National Institutes of Health (GM141544)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
PRMT5, intron splicing, protein arginine methyltransferase, PRMT5 inhibitors, cell cycle defects, cell proliferation, cancer therapy targets

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