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Peer-reviewedCC BY-NC-ND 4.0Communications Biology

PRMT5 inhibition disrupts detained intron splicing and impairs ATR signaling with increased DNA damage

  • Camille H. Cushman1,2,3
  • Colin E. Fowler4,5,6
  • Chiara Mazziotta1,7
  • Mona M. Ahmed1,2,8
  • Ziad Bakouny1,7,9,10
  • Joao A. Paulo11
  • Hembly G. Rivas1,2,12
  • Jacqueline A. Lees4,5
  • James A. DeCaprio1,2,7
  • Jingwei Cheng1,7,13
13 affiliations
  1. 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA USA
  2. 2Committee on Virology, Harvard Graduate School of Arts and Sciences, Cambridge, MA USA
  3. 3Present Address: Viska Bio, Cambridge, MA USA
  4. 4The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA USA
  5. 5Department of Biology, Massachusetts Institute of Technology, Cambridge, MA USA
  6. 6Present Address: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA USA
  7. 7Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
  8. 8Present Address: MD Anderson, Houston, TX USA
  9. 9Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA
  10. 10Present Address: Memorial Sloan Kettering Cancer Center, New York, NY USA
  11. 11Harvard Medical School, Boston, MA USA
  12. 12Present Address: Sarepta Therapeutics, Cambridge, MA USA
  13. 13Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH USA
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Abstract

PRMT5 catalyzes symmetric dimethyl arginine on numerous proteins, with PRMT5 inhibitors (PRMT5i) inducing anti-proliferative effects in preclinical studies. Several models have been proposed to explain sensitivity to PRMT5i including through p53 activation and DNA damage response (DDR) regulation. Here, we interrogate the mechanisms of PRMT5i sensitivity in Merkel cell carcinoma, a neuroendocrine skin cancer sensitive to p53 activation. To identify critical pathways altered by PRMT5i, we performed CRISPR/Cas9 screening, proteomic, and transcriptomic analyses. Our results indicate that PRMT5i sensitivity is independent of p53 activation and is characterized by an increase in detained introns (DIs) and dependency on mRNA processing factors. Sensitivity correlated with elevated basal DI levels and was associated with replication-associated DNA damage accompanied by impaired ATR/CHK1 signaling. These findings are consistent with a threshold model of sensitivity in which excessive DI accumulation is associated with replication-associated DNA damage and apoptosis following PRMT5 inhibition.

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Cite

BibTeXRIS
BibTeX
@article{cushman2026prmt5,
  title = {{PRMT5 inhibition disrupts detained intron splicing and impairs ATR signaling with increased DNA damage}},
  author = {Camille H. Cushman and Colin E. Fowler and Chiara Mazziotta and Mona M. Ahmed and Ziad Bakouny and Joao A. Paulo and Hembly G. Rivas and Jacqueline A. Lees and James A. DeCaprio and Jingwei Cheng},
  journal = {Communications Biology},
  year = {2026},
  month = jul,
  doi = {10.1038/s42003-026-10674-2},
  url = {https://doi.org/10.1038/s42003-026-10674-2},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - PRMT5 inhibition disrupts detained intron splicing and impairs ATR signaling with increased DNA damage
AU  - Camille H. Cushman
AU  - Colin E. Fowler
AU  - Chiara Mazziotta
AU  - Mona M. Ahmed
AU  - Ziad Bakouny
AU  - Joao A. Paulo
AU  - Hembly G. Rivas
AU  - Jacqueline A. Lees
AU  - James A. DeCaprio
AU  - Jingwei Cheng
PY  - 2026
DA  - 2026/07/14
JO  - Communications Biology
DO  - 10.1038/s42003-026-10674-2
UR  - https://doi.org/10.1038/s42003-026-10674-2
AB  - PRMT5 catalyzes symmetric dimethyl arginine on numerous proteins, with PRMT5 inhibitors (PRMT5i) inducing anti-proliferative effects in preclinical studies. Several models have been proposed to explain sensitivity to PRMT5i including through p53 activation and DNA damage response (DDR) regulation. Here, we interrogate the mechanisms of PRMT5i sensitivity in Merkel cell carcinoma, a neuroendocrine skin cancer sensitive to p53 activation. To identify critical pathways altered by PRMT5i, we performed CRISPR/Cas9 screening, proteomic, and transcriptomic analyses. Our results indicate that PRMT5i sensitivity is independent of p53 activation and is characterized by an increase in detained introns (DIs) and dependency on mRNA processing factors. Sensitivity correlated with elevated basal DI levels and was associated with replication-associated DNA damage accompanied by impaired ATR/CHK1 signaling. These findings are consistent with a threshold model of sensitivity in which excessive DI accumulation is associated with replication-associated DNA damage and apoptosis following PRMT5 inhibition.
SN  - 2399-3642
ER  -