Abstract
DNA double-strand breaks (DSBs) are lesions that arise frequently from exposure to damaging agents as well as from ongoing physiological DNA transactions. Mis-repair of DSBs leads to rearrangements and structural variations in chromosomes, including insertions, deletions, and translocations implicated in disease. The DNA damage response (DDR) limits pathologic mutations and large-scale chromosome rearrangements. DSB repair initiates in 2D at DNA lesions with the stepwise recruitment of repair proteins and local chromatin remodeling which facilitates break accessibility. More complex structures are then formed via protein assembly into nanodomains and via genome folding into chromatin loops. Subsequently, 3D reorganization of DSBs is guided by clustering forces which drive the assembly of repair domains harboring multiple lesions. These domains are further stabilized and insulated into condensates via liquid-liquid phase-separation. Here, we discuss the benefits and risks associated with this 3D reorganization of the broken genome.