{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA USA",
    "Committee on Virology, Harvard Graduate School of Arts and Sciences, Cambridge, MA USA",
    "Present Address: Viska Bio, Cambridge, MA USA",
    "The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA USA",
    "Department of Biology, Massachusetts Institute of Technology, Cambridge, MA USA",
    "Present Address: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA USA",
    "Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA",
    "Present Address: MD Anderson, Houston, TX USA",
    "Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA",
    "Present Address: Memorial Sloan Kettering Cancer Center, New York, NY USA",
    "Harvard Medical School, Boston, MA USA",
    "Present Address: Sarepta Therapeutics, Cambridge, MA USA",
    "Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Camille H. Cushman",
      "orcid": "0000-0002-8792-661X"
    },
    {
      "affs": [
        3,
        4,
        5
      ],
      "name": "Colin E. Fowler",
      "orcid": "0000-0002-6281-2851"
    },
    {
      "affs": [
        0,
        6
      ],
      "name": "Chiara Mazziotta"
    },
    {
      "affs": [
        0,
        1,
        7
      ],
      "name": "Mona M. Ahmed",
      "orcid": "0000-0001-7433-8918"
    },
    {
      "affs": [
        0,
        6,
        8,
        9
      ],
      "name": "Ziad Bakouny"
    },
    {
      "affs": [
        10
      ],
      "name": "Joao A. Paulo",
      "orcid": "0000-0002-4291-413X"
    },
    {
      "affs": [
        0,
        1,
        11
      ],
      "name": "Hembly G. Rivas"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Jacqueline A. Lees",
      "orcid": "0000-0001-9451-2194"
    },
    {
      "affs": [
        0,
        1,
        6
      ],
      "name": "James A. DeCaprio",
      "orcid": "0000-0002-0896-167X"
    },
    {
      "affs": [
        0,
        6,
        12
      ],
      "name": "Jingwei Cheng",
      "orcid": "0000-0003-3832-0897"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bftxrv7mapre7.bib",
  "cited_by": 0,
  "doi": "10.1038/s42003-026-10674-2",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13737083/",
  "id": "bftxrv7mapre7",
  "issns": [
    "2399-3642"
  ],
  "landing_url": "https://doi.org/10.1038/s42003-026-10674-2",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Cancer-related gene regulation"
    ]
  ],
  "openalex": "W7168291947",
  "pdf_url": null,
  "pmcid": "PMC13737083",
  "pmid": "42448898",
  "published": "2026-07-14",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/bftxrv7mapre7.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:22:23Z",
      "native_id": "PMC13737083",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s42003-026-10674-2"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Cancer-related gene regulation",
      "subfield": "molecular-biology"
    }
  ],
  "title": "PRMT5 inhibition disrupts detained intron splicing and impairs ATR signaling with increased DNA damage",
  "title_text": "PRMT5 inhibition disrupts detained intron splicing and impairs ATR signaling with increased DNA damage",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:23Z",
  "url": "https://research.draconitic.com/paper/bftxrv7mapre7",
  "venue": "Communications Biology",
  "versions": []
}