Nuclear ARP2/3 drives DNA break clustering for homology-directed repair

Nature. 2018 Jul;559(7712):61-66. doi: 10.1038/s41586-018-0237-5. Epub 2018 Jun 20.


DNA double-strand breaks repaired by non-homologous end joining display limited DNA end-processing and chromosomal mobility. By contrast, double-strand breaks undergoing homology-directed repair exhibit extensive processing and enhanced motion. The molecular basis of this movement is unknown. Here, using Xenopus laevis cell-free extracts and mammalian cells, we establish that nuclear actin, WASP, and the actin-nucleating ARP2/3 complex are recruited to damaged chromatin undergoing homology-directed repair. We demonstrate that nuclear actin polymerization is required for the migration of a subset of double-strand breaks into discrete sub-nuclear clusters. Actin-driven movements specifically affect double-strand breaks repaired by homology-directed repair in G2 cell cycle phase; inhibition of actin nucleation impairs DNA end-processing and homology-directed repair. By contrast, ARP2/3 is not enriched at double-strand breaks repaired by non-homologous end joining and does not regulate non-homologous end joining. Our findings establish that nuclear actin-based mobility shapes chromatin organization by generating repair domains that are essential for homology-directed repair in eukaryotic cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Actin-Related Protein 2-3 Complex / antagonists & inhibitors
  • Actin-Related Protein 2-3 Complex / metabolism*
  • Actins / metabolism
  • Animals
  • Cell Extracts
  • Cell Nucleus / metabolism*
  • Chromatin / metabolism
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair
  • Female
  • Movement
  • Protein Binding
  • Protein Transport
  • Recombinational DNA Repair*
  • Wiskott-Aldrich Syndrome Protein / metabolism
  • Xenopus laevis / genetics*


  • Actin-Related Protein 2-3 Complex
  • Actins
  • Cell Extracts
  • Chromatin
  • Wiskott-Aldrich Syndrome Protein