Multi-scale dynamics of heterochromatin repair

Model of nuclear dynamics following DSB at heterochromatic sites. Following DNA damage, early DSB detection and signaling occur efficiently inside the heterochromatin domain (1). The phase separating properties of repair foci inside a phase separated heterochromatin domain can facilitate focus clustering (2), focus diffusion toward the heterochromatin domain periphery (3), and the spatial and temporal regulation of HR repair. Meanwhile, the entire domain expands (4) while local chromatin changes (5) promote chromatin unfolding to promote repair and dynamics. TADs might organize functional units (loops) for DSB signaling and repair (6), similar to responses in euchromatin. Nuclear actin (F-actin) (7) and myosins drive the directed motion of heterochromatic repair site to the nuclear periphery, where HR repair continues (8) in a ‘safe’ environment. ONM: Outer Nuclear Membrane; INM: Inner Nuclear Membrane. [Display omitted] •Nuclear actin filaments and myosins drive the directed motions of heterochromatic repair sites.•Local and global changes in heterochromatin dynamics promote DNA damage signaling and repair.•Pre-existing and damage-induced changes in the topological organization of chromatin contribute to local dynamics and DSB repair.•Clustering of DSBs promotes early repair steps.•Phase separation influences several aspects of DSB repair, including dynamics. Studies across different organisms show that nuclear architecture and dynamics play central roles in different aspects of homologous recombination (HR) repair. Here we review the most recent discoveries in this field, ranging from directed motions mediating relocalization pathways, to global chromatin mobilization, local DNA looping, and changes in repair focus properties associated with clustering and phase separation. We discuss how these dynamics work in different contexts, including molecular mechanisms and regulatory pathways involved. We specifically highlight how they function in pericentromeric heterochromatin, which presents a unique environment for HR repair given the abundance of repeated DNA sequences prone to aberrant recombination, the 'silent' chromatin state, and the phase separation characterizing this domain.