Journal Article

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

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

2025

Overview

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 ( DIA PH1 L oss-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. DNA double strand break repair pathways ensure genome stability and prevent disease. Here the authors show that the actin nucleating factor DIAPH1 and γ-actin promote homologous recombination (HR)-dependent repair. Inherited mutations in DIAPH1 or ACTG1 give rise to clinical deficits similar to those associated with defective HR.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/89 / 14 / 631/80/304 / 631/80/86/2366 / 96 / 96/109 / 96/35 / Actin / Actins - genetics / Actins - metabolism / Adaptor Proteins, Signal Transducing - deficiency / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Breakage / Cell cycle / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Chromatin / Clustering / Defects / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded / DNA damage / DNA Repair / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Filaments / Formins / Genomes / Homologous Recombination / Humanities and Social Sciences / Humans / Male / MRE11 protein / multidisciplinary / Mutation / Nijmegen breakage syndrome / Nijmegen Breakage Syndrome - genetics / Nijmegen Breakage Syndrome - metabolism / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Science / Science (multidisciplinary) / Stability