{
  "abstract": "The cleavage of membrane-bound phosphoinositides produces inositol polyphosphates (IPs) and pyrophosphates (PP-IPs), small water-soluble signaling molecules that are highly conserved in eukaryotes and play a critical role in cell metabolism. Loss of the inositol pyrophosphate kinase (PP-IPk) Kcs1 and its mammalian ortholog IP6K1 was previously shown to cause hypersensitivity to genotoxic stress and reduced homologous recombination (HR) repair. To identify the mechanism linking PP-IPs to DNA double-strand break (DSB) repair, we combined quantitative proteomics with biochemical, genetic, and cell-cycle analyses in budding yeast. We found that loss of Kcs1, but not the PP-IPk Vip1, caused increased sensitivity to the radiomimetic drug zeocin. kcs1{Delta} cells displayed persistent Rad53 signaling and elevated {gamma}-H2A levels, remaining arrested in G1/S during treatment and accumulating in G2/M for hours after damage removal. Unexpectedly, Kcs1-dependent PP-IPs promoted DSB repair independently of the core HR machinery and of cell-cycle stage. Quantitative proteomics revealed increased levels of PHO pathway proteins in zeocin treated kcs{Delta} cells, and deletion of the CDK inhibitor PHO81 substantially rescued zeocin hypersensitivity, indicating that constitutive inhibition of the Pho80-Pho85 cyclin-dependent kinase underlies the DNA repair defect caused by Kcs1 loss. This function of Pho80-Pho85 was mechanistically distinct from its canonical role in phosphate homeostasis, and partially independent of its connections to Ku80 regulation. Together, our findings identify Kcs1-dependent PP-IP signaling as a new upstream input controlling Pho80-Pho85 activity during the DNA damage response, establishing an HR-independent axis for genome maintenance and linking PP-IP metabolism to the DNA damage response in eukaryotic cells.",
  "abstract_shown": true,
  "affiliations": [
    "Universidade Federal de Sao Paulo"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "G. M. Panessa"
    },
    {
      "name": "P. P. Sforsin"
    },
    {
      "name": "M. M. Wagner"
    },
    {
      "name": "G. Monteiro"
    },
    {
      "name": "M. B. Smolka"
    },
    {
      "affs": [
        0
      ],
      "name": "J. R. R. Cussiol"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c0zcwgyjacmnh.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.07.751851",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.751851v1.full",
  "id": "c0zcwgyjacmnh",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.751851v1",
  "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",
      "cell biology"
    ],
    [
      "openalex",
      "1312|DNA Repair Mechanisms"
    ]
  ],
  "openalex": "W7221098895",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.751851v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/c0zcwgyjacmnh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:48Z",
      "native_id": "10.64898/2026.10.07.751851",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.07.751851v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:cell biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "Kcs1-dependent inositol pyrophosphates promote DNA double-strand break repair via Pho80-Pho85 in budding yeast",
  "title_text": "Kcs1-dependent inositol pyrophosphates promote DNA double-strand break repair via Pho80-Pho85 in budding yeast",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:57Z",
  "url": "https://research.draconitic.com/paper/c0zcwgyjacmnh",
  "venue": "bioRxiv",
  "versions": []
}