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

Year: 2025

Type: article

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.

Source: Nature Communications

DOI: 10.1038/s41467-025-59553-0

Institutions: University of Birmingham, New York University, Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Boston University, University of Kent, UCL Queen Square Institute of Neurology, University College London, University Hospital Carl Gustav Carus, Technische Universität Dresden, Guy's Hospital, King's College London, University of the Witwatersrand, St. Jude Children's Research Hospital, King Fahd Medical City, National Institutes of Health, National Institutes of Health Clinical Center, Istituto Giannina Gaslini, University of Genoa, University of Rome Tor Vergata, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, Sheffield Children's NHS Foundation Trust, Sheffield Children's Hospital, Great Ormond Street Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, Aga Khan University, University of Manchester, National Research Centre, University of Wrocław, Medizinische Hochschule Hannover

Language: English

Topic: DNA Repair Mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $6,990

Funders: 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, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Environmental Health Sciences

OpenAlex ID: W4410360745