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

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, Valentina Galassi Deforie, Reza Maroofian, Stephanie Efthymiou, Andrea Meinhardt, Christopher G. Mathew, Michael A. Simpson, Heather C. Mefford, Eissa A. Faqeih, Sergio D. Rosenzweig, Stefano Volpi, Gigliola Matteo, Caterina Cancrini, Annarita Scardamaglia, Fiona Shackley, E. Graham Davies, Shahnaz Ibrahim, Peter D. Arkwright, Maha S. Zaki, Tatjana Stankovic, A. Malcolm R. Taylor, Antonina J. Mazur, Nataliya Donato, Henry Houlden, Eli Rothenberg and Grant S. Stewart ()
Additional contact information
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
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
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
Gigliola Matteo: Tor Vergata University
Caterina Cancrini: Tor Vergata University
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

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59553-0

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