{
  "abstract": "Dual PARP1/2 inhibitors (PARPi) selectively eliminate BRCA1/2-deficient cancers and represent the first targeted therapy for homologous recombination (HR)-deficient cancers. However, their use in maintenance therapy is limited by severe anemia and an increased risk for therapy-related leukemia. These toxicities are unexpected because PARP1 loss, which eliminates most DNA-damage-induced PARylation, does not cause anemia in mice. In contrast, PARP2 loss or catalytic inactivation causes anemia, motivating the development of PARP1-selective inhibitors. Using wild-type (WT), Parp1-/- and Parp2-/- mice, we show that hematopoietic toxicity of FDA-approved PARPi is driven primarily by inactive PARP1 rather than PARP2 inhibition. Accordingly, PARP1-selective inhibitors also cause PARP1-dependent anemia. Somatic expression of catalytically inactive Parp1 (Parp1E988A) causes lethal bone marrow failure, not found with somatic deletion of both Parp1&2. Mechanistically, inactive PARP1 obstructs the repair of diverse DNA lesions, including gaps, nicks, and Top1-cc, in contrast to the nick-selectivity of Parp2. In cells, inactive PARP1 compromises PARP2 recruitment to DNA lesions and causes severe genomic instability and mitotic bridges absent in Parp1&2-null cells. Thus, PARPi-induced hematopoietic toxicity is driven primarily by PARP1 inactivation, informing the design and use of next-generation PARP inhibitors.",
  "abstract_shown": true,
  "affiliations": [
    "Columbia University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "X. Lin"
    },
    {
      "name": "Z. Shao"
    },
    {
      "name": "D. Yaneva"
    },
    {
      "name": "W. Jiang"
    },
    {
      "name": "D. Menolfi"
    },
    {
      "name": "S. K. Bhandari"
    },
    {
      "name": "B. J. Lee"
    },
    {
      "name": "M. Schmucker"
    },
    {
      "name": "F. Yaneva"
    },
    {
      "name": "A. E. Tomkinson"
    },
    {
      "name": "J. Stingele"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Zha"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5nbvjdjwmgpd2.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.21.753312",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.21.753312v1.full",
  "id": "5nbvjdjwmgpd2",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.21.753312v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2730|PARP inhibition in cancer therapy"
    ]
  ],
  "openalex": "W7214021147",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.21.753312v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-21",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5nbvjdjwmgpd2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:57Z",
      "native_id": "10.64898/2026.09.21.753312",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.21.753312v2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Catalytically inactive PARP1 protein drives PARP inhibitor induced hematological toxicity",
  "title_text": "Catalytically inactive PARP1 protein drives PARP inhibitor induced hematological toxicity",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:37Z",
  "url": "https://research.draconitic.com/paper/5nbvjdjwmgpd2",
  "venue": "bioRxiv",
  "versions": []
}