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Inherited deficiency of DIAPH1 identifies a DNA double strand break repair pathway regulated by γ-actin

Author

Listed:
  • Beth L. Woodward

    (University of Birmingham)

  • Sudipta Lahiri

    (New York University School of Medicine)

  • Anoop S. Chauhan

    (University of Birmingham)

  • Marcos Rios Garcia

    (University of Birmingham
    University of Santiago de Compostela)

  • Lucy E. Goodley

    (University of Birmingham)

  • Thomas L. Clarke

    (Boston University Chobanian and Avedisian School of Medicine)

  • Mohinder Pal

    (University of Kent)

  • Angelo Agathanggelou

    (University of Birmingham)

  • Satpal S. Jhujh

    (University of Birmingham)

  • Anil N. Ganesh

    (University of Birmingham)

  • Fay M. Hollins

    (University of Birmingham)

  • Valentina Galassi Deforie

    (University College London)

  • Reza Maroofian

    (University College London)

  • Stephanie Efthymiou

    (University College London)

  • Andrea Meinhardt

    (University Hospital Carl Gustav Carus at TUD Dresden University of Technology and Faculty of Medicine of TUD Dresden University of Technology)

  • Christopher G. Mathew

    (University of the Witwatersrand
    Guy’s Hospital)

  • Michael A. Simpson

    (Guy’s Hospital)

  • Heather C. Mefford

    (St. Jude Children’s Hospital)

  • Eissa A. Faqeih

    (King Fahad Medical City, Children’s Hospital,)

  • Sergio D. Rosenzweig

    (National Institutes of Health)

  • Stefano Volpi

    (UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini
    Università degli Studi di Genova)

  • Gigliola Matteo

    (Tor Vergata University
    Research Unit of Primary Immunodeficiencies, Unit of Clinical Immunology and Vaccinology, Scientific Institute for Research and Healthcare (IRCCS) Bambino Gesù Children Hospital)

  • Caterina Cancrini

    (Tor Vergata University
    Research Unit of Primary Immunodeficiencies, Unit of Clinical Immunology and Vaccinology, Scientific Institute for Research and Healthcare (IRCCS) Bambino Gesù Children Hospital)

  • Annarita Scardamaglia

    (University College London)

  • Fiona Shackley

    (Paediatric Immunology, Allergy and Infectious Diseases, Sheffield Children’s Hospital NHS Foundation Trust)

  • E. Graham Davies

    (Great Ormond Street Hospital for Children NHS Foundation Trust)

  • Shahnaz Ibrahim

    (Aga Khan University)

  • Peter D. Arkwright

    (University of Manchester)

  • Maha S. Zaki

    (Human Genetics and Genome Research Division, National Research Centre)

  • Tatjana Stankovic

    (University of Birmingham)

  • A. Malcolm R. Taylor

    (University of Birmingham)

  • Antonina J. Mazur

    (University of Wroclaw)

  • Nataliya Donato

    (Institute for Human Genetics, Hannover Medical School)

  • Henry Houlden

    (University College London)

  • Eli Rothenberg

    (New York University School of Medicine)

  • Grant S. Stewart

    (University of Birmingham)

Abstract

DNA double strand break repair (DSBR) represents a fundamental process required to maintain genome stability and prevent the onset of disease. Whilst cell cycle phase and the chromatin context largely dictate which repair pathway is utilised to restore damaged DNA, it has been recently shown that nuclear actin filaments play a major role in clustering DNA breaks to facilitate DSBR by homologous recombination (HR). However, the mechanism with which nuclear actin and the different actin nucleating factors regulate HR is unclear. Interestingly, patients with biallelic mutations in the actin nucleating factor DIAPH1 exhibit a striking overlap of clinical features with the HR deficiency disorders, Nijmegen Breakage Syndrome (NBS) and Warsaw Breakage Syndrome (WABS). This suggests that DIAPH1 may play a role in regulating HR and that some of the clinical deficits associated with DIAPH1 mutations may be caused by an underlying DSBR defect. In keeping with this clinical similarity, we demonstrate that cells from DIAL (DIAPH1 Loss-of-function) Syndrome patients display an HR repair defect comparable to loss of NBS1. Moreover, we show that this DSBR defect is also observed in a subset of patients with Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome associated with mutations in ACTG1 (γ-actin) but not ACTB (β-actin). Lastly, we demonstrate that DIAPH1 and γ-actin promote HR-dependent repair by facilitating the relocalisation of the MRE11/RAD50/NBS1 complex to sites of DNA breaks to initiate end-resection. Taken together, these data provide a mechanistic explanation for the overlapping clinical symptoms exhibited by patients with DIAL syndrome, BWCFF syndrome and NBS.

Suggested Citation

  • Beth L. Woodward & Sudipta Lahiri & Anoop S. Chauhan & Marcos Rios Garcia & Lucy E. Goodley & Thomas L. Clarke & Mohinder Pal & Angelo Agathanggelou & Satpal S. Jhujh & Anil N. Ganesh & Fay M. Hollins, 2025. "Inherited deficiency of DIAPH1 identifies a DNA double strand break repair pathway regulated by γ-actin," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59553-0
    DOI: 10.1038/s41467-025-59553-0
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