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

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.