{
  "abstract": "Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that Trimethyllysine Hydroxylase Epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis and provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA",
    "Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA",
    "Tsinghua University, Beijing, China",
    "Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA",
    "Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA",
    "Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA",
    "Department of Radiation Oncology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA",
    "Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA",
    "Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA",
    "Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA",
    "Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA",
    "Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA",
    "Biostatistics Facility, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA",
    "Department of Medicine, Division of Hematology/Oncology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA",
    "Department of Computational & Systems Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA",
    "Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA",
    "Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. NateWSnyder@temple.edu",
    "Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. kaird@wistar.org",
    "Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA. kaird@wistar.org"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 39,
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      "name": "Baixue Yang"
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      "name": "Hui Wang"
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      "name": "Naveen Kumar Tangudu",
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        1
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      "name": "Aidan R. Cole",
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        4
      ],
      "name": "Julie A. Disharoon",
      "orcid": "0000-0002-4262-6496"
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        0
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      "name": "Richard S. Fang",
      "orcid": "0009-0001-9559-9735"
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      "name": "Evan Levasseur",
      "orcid": "0009-0008-4698-9551"
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      "name": "Miho Naruse"
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      "name": "Zhentai Huang",
      "orcid": "0000-0002-8102-464X"
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      "name": "Emily Megill",
      "orcid": "0000-0002-0244-8779"
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      "name": "Daniel S. Kantner",
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      "name": "Adam G. Chatoff",
      "orcid": "0000-0002-7954-9527"
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        3
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      "name": "Hafsah Ahmad"
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      "name": "Mariola M. Marcinkiewicz",
      "orcid": "0009-0002-3950-4081"
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      "name": "Sarah Graff",
      "orcid": "0000-0002-4999-5454"
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        5
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      "name": "Ellen De Pieri",
      "orcid": "0000-0002-2449-1225"
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      "name": "Andrea Andress Huacachino",
      "orcid": "0000-0002-4084-3411"
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      "name": "Frank P. Vendetti",
      "orcid": "0009-0000-7480-355X"
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      "name": "Jeff Danielson"
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        7
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      "name": "Erika S. Dahl",
      "orcid": "0000-0001-6506-9103"
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      "name": "Jennifer L Pennise"
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      "name": "Esther Elishaev"
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        3,
        9
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      "name": "Alison Jaccard",
      "orcid": "0000-0002-7737-3118"
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      "name": "Lauren Borho",
      "orcid": "0009-0005-1253-5322"
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        11
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      "name": "Miriam D. Post",
      "orcid": "0000-0001-7220-8247"
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    {
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        12
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      "name": "Kristine Cooper"
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      "name": "Francesmary Modugno",
      "orcid": "0000-0003-0637-1534"
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      "name": "Nadine Hempel",
      "orcid": "0000-0002-5574-8783"
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      "name": "Wayne Stallaert",
      "orcid": "0000-0001-8064-6503"
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      "name": "Christopher J. Bakkenist",
      "orcid": "0000-0001-9672-0886"
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      "name": "Simone Sidoli",
      "orcid": "0000-0001-9073-6641"
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      "name": "Kathryn E. Wellen",
      "orcid": "0000-0002-2281-0042"
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      "name": "Benjamin Guy Bitler",
      "orcid": "0000-0002-5809-5271"
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      "name": "David T. Long",
      "orcid": "0000-0001-9232-0316"
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      "name": "Nathaniel W. Snyder",
      "orcid": "0000-0001-5643-8747"
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      "name": "Katherine M. Aird",
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  "bibtex": "https://research.draconitic.com/paper/4hexankt8n2e6.bib",
  "cited_by": 10,
  "doi": "10.1038/s41586-026-10584-7",
  "fulltext_url": null,
  "id": "4hexankt8n2e6",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10584-7",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|DNA Repair Mechanisms"
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  "openalex": "W7162501421",
  "pdf_url": null,
  "pmcid": "PMC10871207",
  "pmid": "38370789",
  "published": "2026-05-27",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/4hexankt8n2e6.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T13:20:47Z",
      "native_id": "W7162501421",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10584-7"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|DNA Repair Mechanisms",
      "subfield": "molecular-biology"
    }
  ],
  "title": "αKG-mediated carnitine synthesis drives DNA repair via histone acetylation",
  "title_text": "αKG-mediated carnitine synthesis drives DNA repair via histone acetylation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:30Z",
  "url": "https://research.draconitic.com/paper/4hexankt8n2e6",
  "venue": "Nature",
  "versions": []
}