{
  "abstract": "ATR inhibition has been proposed as a strategy for tumors under replication stress or those harboring ATM deficiency. However, anti-tumor activity is limited by DNA-PK and ATM compensation. Here, we have delineated distinct roles for DNA-PK and ATM during ATR inhibitor exposure. Both kinases are activated in a cell cycle-dependent manner at the S/G2 boundary following ATR inhibition. DNA-PK imposes the S/G2 checkpoint and promotes completion of DNA replication, whereas ATM detects persistent aberrant DNA replication structures with associated DNA damage in late S and G2/M to establish a G2/M checkpoint promoting DNA repair. In ATM-deficient cells and patient tumors, DNA-PK is activated following ATR inhibition and assumes greater versatility by not only enforcing the S/G2 checkpoint but also by detecting aberrant replication structures in S phase in place of ATM, allowing cells to tolerate ATR inhibition. Consequently, DNA-PK inhibition synergizes with ATR inhibition in ATM-deficient cells and enhances ATR inhibitor efficacy in ATM-deficient PDX models. These data support clinical evaluation of combined ATR and DNA-PK inhibition in ATM-deficient cancers.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "Timothy B. Branigan",
      "orcid": "0009-0000-7301-8445"
    },
    {
      "name": "Roshen Alharthi"
    },
    {
      "name": "Bose S. Kochupurakkal",
      "orcid": "0000-0001-8929-3070"
    },
    {
      "name": "Jie Hao",
      "orcid": "0000-0002-4610-0563"
    },
    {
      "name": "Steffie Revia",
      "orcid": "0000-0003-4088-3250"
    },
    {
      "name": "Joachim Albers",
      "orcid": "0000-0003-0582-1863"
    },
    {
      "name": "Mu-Yan Cai"
    },
    {
      "name": "Yuqing Jiao"
    },
    {
      "name": "Kelsey McQueen"
    },
    {
      "name": "Sirisha Mukkavalli",
      "orcid": "0000-0002-8875-7985"
    },
    {
      "name": "Ian A. Roundtree",
      "orcid": "0000-0002-9791-054X"
    },
    {
      "name": "Gregory M. Cote",
      "orcid": "0000-0003-0181-886X"
    },
    {
      "name": "Prafulla C. Gokhale",
      "orcid": "0000-0002-1974-5921"
    },
    {
      "name": "Kalindi Parmar",
      "orcid": "0000-0002-9522-1716"
    },
    {
      "name": "Alan D. D’Andrea",
      "orcid": "0000-0001-6168-6294"
    },
    {
      "name": "Astrid Zimmermann"
    },
    {
      "name": "Geoffrey I. Shapiro",
      "orcid": "0000-0002-3331-4095"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/56x1b4am7eydh.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.25.761677",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.25.761677v1.full",
  "id": "56x1b4am7eydh",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.25.761677v1",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|DNA Repair Mechanisms"
    ]
  ],
  "openalex": "W7224123020",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.25.761677v1.full.pdf",
  "pmcid": "PMC13733874",
  "pmid": "42990312",
  "published": "2026-10-25",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/56x1b4am7eydh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:58Z",
      "native_id": "10.64898/2026.10.25.761677",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.25.761677v1"
    },
    {
      "first_seen": "2026-11-08T12:23:33Z",
      "native_id": "PMC13733874",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.25.761677"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "DNA-PK enforces the S/G2 checkpoint in ATM-deficient cells to limit ATR inhibitor efficacy",
  "title_text": "DNA-PK enforces the S/G2 checkpoint in ATM-deficient cells to limit ATR inhibitor efficacy",
  "type": "preprint",
  "updated_at": "2026-11-08T12:23:33Z",
  "url": "https://research.draconitic.com/paper/56x1b4am7eydh",
  "venue": "bioRxiv",
  "versions": []
}