Integration of DNA damage responses with dynamic spatial genome organization.

The maintenance of genome stability and cellular homeostasis depends on the temporal and spatial coordination of successive events constituting the classical DNA damage response (DDR). Recent findings suggest close integration and coordination of DDR signaling with specific cellular processes. The mechanisms underlying such coordination remain unclear. We review emerging crosstalk between DNA repair factors, chromatin remodeling, replication, transcription, spatial genome organization, cytoskeletal forces, and liquid-liquid phase separation (LLPS) in mediating DNA repair. We present an overarching DNA repair framework within which these dynamic processes intersect in nuclear space over time. Collectively, this interplay ensures the efficient assembly of DNA repair proteins onto shifting genome structures to preserve genome stability and cell survival.