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

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.

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Journal
Nature Communications
Published
2025-05-14
DOI
https://doi.org/10.1038/s41467-025-59553-0
Primary Topic
DNA Repair Mechanisms
Type
article
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0.00

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article

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

E. Graham Davies, Valentina Galassi Deforie, Nataliya Di Donato, Fay Marie Hollins et al.
Nature Communications
DNA Repair Mechanisms
article

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

E. Graham Davies, Valentina Galassi Deforie, Nataliya Di Donato, Fay Marie Hollins, Annarita Scardamaglia, Thomas L. Clarke, Beth L. Woodward, Maha Saad Zaki, Mohinder Pal, Antonina Joanna Mazur, Christopher G. Mathew, Stéphanie Efthymiou, Satpal S. Jhujh, Peter D. Arkwright, Heather C. Mefford, Michael A. Simpson, Angelo Agathanggelou, Shahnaz Ibrahim, Stefano Volpi, Sudipta Lahiri, Sergio D. Rosenzweig, Caterina Cancrini, Anoop Singh Chauhan, Tatjana Stanković, Grant S. Stewart, Anil Ganesh, Fiona Shackley, Gigliola Di Matteo, Eissa Faqeih, Eli Rothenberg, Henry Houlden, Reza Maroofian, A. Malcolm R. Taylor, Andrea Meinhardt, Marcos Rios Garcia, Lucy E Goodley
article en

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.

Nature CommunicationsVol. 16(1)
Boston University (US), University of Rome Tor Vergata (IT), Aga Khan University (PK), Guy's Hospital (GB), St. Jude Children's Research Hospital (US), King's College London (GB), University of the Witwatersrand (ZA), Universidade de Santiago de Compostela (ES), University of Kent (GB), University of Wrocław (PL), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), Istituto Giannina Gaslini (IT), King Fahd Medical City (SA), University of Manchester (GB), Medizinische Hochschule Hannover (DE), Bambino Gesù Children's Hospital (IT), National Research Centre (EG), Cancer Research UK Clinical Trials Unit (GB), National Hospital for Neurology and Neurosurgery (GB), Istituti di Ricovero e Cura a Carattere Scientifico (IT), National Institutes of Health Clinical Center (US), University Hospital Carl Gustav Carus (DE), Sheffield Children's Hospital (GB), University College London (GB), New York University (US), University of Birmingham (GB), University of Genoa (IT)
Wellcome Trust, UK Research and Innovation, Cancer Research UK, National Institute for Health and Care Research, University College London, Lister Institute of Preventive Medicine, University College London Hospitals NHS Foundation Trust, National Institutes of Health, Medical Research Council, Agencia Estatal de Investigación
Good health and well-being
Openalex Percentile: Top 90%
DNA Repair Mechanisms
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