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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

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Communications Biology
|July 14, 2026
PubMed

Insights

PRMT5 inhibitors (PRMT5i) cause cancer cell death by increasing detained introns (DIs), impacting mRNA processing. Sensitivity is linked to DNA damage and impaired signaling, not p53 activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Protein arginine methyltransferase 5 (PRMT5) inhibition shows anti-proliferative effects.
  • Proposed mechanisms for PRMT5 inhibitor (PRMT5i) sensitivity involve p53 activation and DNA damage response (DDR).

Purpose of the Study:

  • To investigate the mechanisms of PRMT5i sensitivity in Merkel cell carcinoma.
  • To identify pathways critical for PRMT5i sensitivity independent of p53 activation.

Main Methods:

  • CRISPR/Cas9 screening
  • Proteomic analysis
  • Transcriptomic analysis

Main Results:

  • PRMT5i sensitivity is independent of p53 activation.
  • PRMT5i treatment increases detained introns (DIs) and dependency on mRNA processing factors.
  • Sensitivity correlates with elevated basal DI levels, replication-associated DNA damage, and impaired ATR/CHK1 signaling.

Conclusions:

  • PRMT5i sensitivity in Merkel cell carcinoma is linked to accumulated DIs and impaired DNA damage response.
  • A threshold model explains sensitivity, where excessive DI accumulation leads to DNA damage and apoptosis upon PRMT5 inhibition.

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