Multiscale reorganization of the genome following DNA damage facilitates chromosome translocations via nuclear actin polymerization

Nat Struct Mol Biol. 2023 Jan;30(1):99-106. doi: 10.1038/s41594-022-00893-6. Epub 2022 Dec 23.


Nuclear actin-based movements have been shown to orchestrate clustering of DNA double-strand breaks (DSBs) into homology-directed repair domains. Here we describe multiscale three-dimensional genome reorganization following DNA damage and analyze the contribution of the nuclear WASP-ARP2/3-actin pathway toward chromatin topology alterations and pathologic repair. Hi-C analysis reveals genome-wide, DNA damage-induced chromatin compartment flips facilitated by ARP2/3 that enrich for open, A compartments. Damage promotes interactions between DSBs, which in turn facilitate aberrant, actin-dependent intra- and inter-chromosomal rearrangements. Our work establishes that clustering of resected DSBs into repair domains by nuclear actin assembly is coordinated with multiscale alterations in genome architecture that enable homology-directed repair while also increasing nonhomologous end-joining-dependent translocation frequency.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins* / metabolism
  • Chromatin
  • DNA Damage
  • DNA End-Joining Repair
  • DNA Repair
  • Humans
  • Polymerization
  • Translocation, Genetic*


  • Actins
  • Chromatin