{
  "abstract": "Specific inherited mutations of BRCA1 compromise homologous recombination repair and increase the risk of cancer. Here, we employ a panel of isogenic chicken DT40 cell lines for the comparative study of the main BRCA1 protein domains and of common BRCA1 founder mutations in genome stability and DNA repair. Whole genome sequencing of cell clones demonstrates that the L1407P-equivalent coiled coil domain variant is a separation-of-function mutant with an increased rate of base substitution mutagenesis but not of deletions or large-scale genomic instability, reflecting its proficiency in repairing DNA double strand breaks and promoting sister chromatid exchanges. The BRCA1 coiled coil domain mediates interaction with PALB2, and PALB2 coiled coil domain mutations also primarily affect base substitution mutagenesis. In contrast, truncating and missense mutations in the RING and BRCT domains affect all functions of BRCA1, inducing larger deletions and rearrangements typical of BRCA1 loss. PARP inhibitor sensitivity is marginal in the coiled coil domain mutants, instead it correlates with deletion mutagenesis, degradation of stalled replication forks, and impaired RAD51 loading following topoisomerase I inhibition. Our results suggest a specific function for the BRCA1-PALB2 interaction in promoting error-free DNA damage bypass as an alternative to mutagenic translesion DNA synthesis.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary.",
    "IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy.",
    "Doctoral School of Biology, ELTE Eötvös Loránd University, Budapest, Hungary.",
    "Molecular Medicine Division, Semmelweis University Doctoral School, Semmelweis University, Budapest, Hungary.",
    "Danish Cancer Institute, Copenhagen, Denmark.",
    "Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.",
    "Department of Bioinformatics, Semmelweis University, Budapest, Hungary.",
    "Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), Pavia, Italy.",
    "Research Center One Health Ruhr, University Alliance Ruhr, Faculty of Biology, University of Duisburg-Essen, Essen, Germany.",
    "Johns Hopkins University School of Medicine, Baltimore, MD, USA. aricha58@jhu.edu.",
    "Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary. szuts.david@ttk.hu.",
    "National Laboratory for Drug Research and Development, Budapest, Hungary. szuts.david@ttk.hu."
  ],
  "article_type": "research support, non u.s. gov't",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Bernadett Szikriszt"
    },
    {
      "affs": [
        0
      ],
      "name": "Eszter Németh"
    },
    {
      "affs": [
        1
      ],
      "name": "Bayejid Hosen"
    },
    {
      "affs": [
        0
      ],
      "name": "Michał Krawczyk"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Regina Martinek",
      "orcid": "0009-0000-5502-3531"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Bendegúz Szabó",
      "orcid": "0009-0000-7668-5200"
    },
    {
      "affs": [
        0
      ],
      "name": "Ádám Póti"
    },
    {
      "affs": [
        0
      ],
      "name": "Zoltán Szeltner"
    },
    {
      "affs": [
        0
      ],
      "name": "György Várady"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Zsófia Sztupinszki"
    },
    {
      "affs": [
        4,
        5,
        6
      ],
      "name": "Zoltan Szallasi",
      "orcid": "0000-0001-5395-7509"
    },
    {
      "affs": [
        1,
        7,
        8
      ],
      "name": "Dana Branzei",
      "orcid": "0000-0002-0544-4888"
    },
    {
      "affs": [
        9
      ],
      "name": "Andrea L Richardson",
      "orcid": "0000-0001-5221-1094"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Dávid Szüts",
      "orcid": "0000-0001-7985-0136"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ae6g43bqpqk5t.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-77330-5",
  "fulltext_url": "https://europepmc.org/articles/PMC13687062",
  "id": "ae6g43bqpqk5t",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://europepmc.org/article/MED/42907458",
  "language": "eng",
  "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": [
    [
      "openalex",
      "1312|DNA Repair Mechanisms"
    ]
  ],
  "openalex": "W7214004310",
  "pdf_url": "https://europepmc.org/articles/PMC13687062?pdf=render",
  "pmcid": "PMC13687062",
  "pmid": "42907458",
  "published": "2026-09-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/ae6g43bqpqk5t.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:57Z",
      "native_id": "MED:42907458",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42907458"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|DNA Repair Mechanisms",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Patient-derived separation-of-function mutations reveal specific role for BRCA1 coiled coil domain in genome stability.",
  "title_text": "Patient-derived separation-of-function mutations reveal specific role for BRCA1 coiled coil domain in genome stability.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:57Z",
  "url": "https://research.draconitic.com/paper/ae6g43bqpqk5t",
  "venue": "Nature communications",
  "versions": []
}