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<p>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 <i>DIAPH1</i> exhibit a striking overlap of clinical features with the HR deficiency disorders, Nijmegen Breakage Syndrome (NBS) and Warsaw Breakage Syndrome&#xa0;(WABS). This suggests that DIAPH1 may play a role in regulating HR and that some of the clinical deficits associated with <i>DIAPH1</i> mutations may be caused by an underlying DSBR defect. In keeping with this clinical similarity, we demonstrate that cells from DIAL (<Emphasis Type="Underline">DIA</Emphasis>PH1 <Emphasis Type="Underline">L</Emphasis>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 <i>ACTG1</i> (γ-actin) but not <i>ACTB</i> (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.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年5月14日

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  • 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 Di 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 Di Donato,
  • Henry Houlden,
  • Eli Rothenberg,
  • Grant S. Stewart

摘要

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.