Nuclear and genome dynamics underlying DNA double-strand break repair

Changes in nuclear shape and in the spatial organization of chromosomes in the nucleus commonly occur in cancer, ageing and other clinical contexts that are characterized by increased DNA damage. However, the relationship between nuclear architecture, genome organization, chromosome stability and health remains poorly defined. Studies exploring the connections between the positioning and mobility of damaged DNA relative to various nuclear structures and genomic loci have revealed nuclear and cytoplasmic processes that affect chromosome stability. In this Review, we discuss the dynamic mechanisms that regulate nuclear and genome organization to promote DNA double-strand break (DSB) repair, genome stability and cell survival. Genome dynamics that support DSB repair rely on chromatin states, repair-protein condensates, nuclear or cytoplasmic microtubules and actin filaments, kinesin or myosin motor proteins, the nuclear envelope, various nuclear compartments, chromosome topology, chromatin loop extrusion and diverse signalling cues. These processes are commonly altered in cancer and during natural or premature ageing. Indeed, the reshaping of the genome in nuclear space during DSB repair points to new avenues for therapeutic interventions that may take advantage of new cancer cell vulnerabilities or aim to reverse age-associated defects.