Modalities and genetic requirements for DSB movement. A mammalian cell nucleus is shown in the center with damaged and undamaged sites indicated by red and yellow circles, respectively. Dashed lines indicate sister chromatids, while homologous chromosomes share identical colors. Different modalities for DNA DSB mobility are shown: (A) clustering of HDR breaks in mammalian cells, (B) relocalization of heterochromatic DSB in Drosophila, (C) cytoplasmic microtubule-driven motion of damaged telomeres, (D) limited mobility of NHEJ breaks, and (E) chromatin remodeling–dependent DSB motion. The initial steps of HDR are shown. The MRN/CtIP nuclease initiates DNA end-resection at sites of DNA DSBs marked by γH2AX. Further resection is brought about by additional nucleases, including Exo1. The resulting ssDNA 3′ overhang is coated with the trimeric ssDNA-binding protein RPA followed by the assembly of the Rad51 recombinase. (A) Rad51 is associated with enhanced DSB mobility in yeast and mammalian cells. Rad51, Mre11, and CtIP are required for this enhanced mobility. (B) In Drosophila, the activities of MRN, CtIP, Exo1, and Blm are required for DSB relocation outside the heterochromatic domain, which takes place before the assembly of Rad51 chromatin filaments (red arrow). Movements in A and B both require nuclear actin polymerization. (C) Microtubule (MT) polymerization in the cytoplasm transduces forces to damaged chromatin that generates movement. Microtubule-driven forces are relayed via the LINC complex. (D) DSBs that undergo NHEJ have limited mobility. (E) DSBs recruit chromatin remodeling complexes, which reorganize nucleosomes, thereby increasing access of repair machinery to the damaged site. Chromatin decompaction facilitated by chromatin remodelers promotes chromosome mobility.