{
  "abstract": "Pancreatic ductal adenocarcinoma (PDAC) exhibits profound metabolic rewiring and strong resistance to DNA-damaging therapies, yet how metabolic pathways regulate genome maintenance remains poorly understood. The hexosamine biosynthetic pathway (HBP) integrates nutrient availability with protein glycosylation through production of UDP-GlcNAc, but its role in DNA damage response (DDR) regulation is unclear. Here we show that inhibition of the HBP enzyme phosphoglucomutase-3 (PGM3) reduces DNA repair capacity in pancreatic cancer cells. Transcriptomic and functional analyses reveal that the selective PGM3 inhibitor FR054 amplifies gemcitabine-induced replication stress, disrupts ATR-CHK1 and ATM-CHK2 checkpoint signaling, and selectively impairs homologous recombination. Glycoproteomic profiling identifies the AAA+ ATPase RUVBL2 as a key metabolic-DDR node. Gemcitabine increases RUVBL2 O-GlcNAcylation, with Thr81 identified as a modified residue within the Walker A nucleotide-binding motif. Structural modelling predicts that Thr81 O-GlcNAcylation stabilizes the RUVBL1-RUVBL2 complex without compromising ATP-Mg engagement. PGM3 inhibition and Thr81 mutation similarly reduced ATR and ATM abundance and promoted persistent DNA damage, supporting a role for RUVBL2 Thr81 O-GlcNAcylation in sustaining checkpoint signalling and genome stability. Consequently, PGM3 inhibition induces a BRCAness-like state that sensitizes pancreatic cancer cells to PARP inhibition, both in vitro and in vivo, as well as to ionizing radiation. These findings reveal a nutrient-sensitive mechanism linking protein glycosylation to genome maintenance and identify HBP-dependent DNA repair as a potentially actionable vulnerability in pancreatic cancer.",
  "abstract_shown": true,
  "affiliations": [
    "University of Milano-Bicocca, Milano, Italy"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "name": "B. Zerbato"
    },
    {
      "name": "G. Taverna"
    },
    {
      "name": "M. La Chimia"
    },
    {
      "name": "M. Pontoriero"
    },
    {
      "name": "S. Lombardi"
    },
    {
      "name": "L. Taglietti"
    },
    {
      "name": "K. Deng"
    },
    {
      "name": "G. C. Perrone"
    },
    {
      "name": "S. Hakkola"
    },
    {
      "name": "A. Vuori"
    },
    {
      "name": "T. Syriala"
    },
    {
      "name": "E. De Billy"
    },
    {
      "name": "S. M. Barabino"
    },
    {
      "name": "C. Bragato"
    },
    {
      "name": "C. L. Pierri"
    },
    {
      "name": "B. La Ferla"
    },
    {
      "name": "A. Urbanucci"
    },
    {
      "name": "D. Scumaci"
    },
    {
      "affs": [
        0
      ],
      "name": "F. Chiaradonna"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c92yk41kf24zy.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.31.746486",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.31.746486v1.full",
  "id": "c92yk41kf24zy",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.31.746486v1",
  "language": null,
  "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"
    ],
    [
      "openalex",
      "1312|DNA Repair Mechanisms"
    ]
  ],
  "openalex": "W7204915930",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.31.746486v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-31",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/c92yk41kf24zy.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:13Z",
      "native_id": "10.64898/2026.08.31.746486",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.31.746486v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "PGM3 inhibition rewires RUVBL2-dependent DNA repair and induces a BRCAness-like state in pancreatic cancer cells",
  "title_text": "PGM3 inhibition rewires RUVBL2-dependent DNA repair and induces a BRCAness-like state in pancreatic cancer cells",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:13Z",
  "url": "https://research.draconitic.com/paper/c92yk41kf24zy",
  "venue": "bioRxiv",
  "versions": []
}