DNA double-strand breaks (DSBs) are among the most cytotoxic and most frequent lesions that arise in the mammalian genome; they occur as a result of both external insults and internal metabolic activities. Failures in damage signalling and repair of DSBs can result in permanent cell cycle arrest, cellular senescence, cell death or the accumulation of mutations and genomic instability - events that ultimately disrupt tissue homeostasis. To reduce these detrimental outcomes, cells have evolved a sophisticated and tightly coordinated network of mechanisms for detecting, signalling and repairing DNA lesions, collectively known as the DNA damage response (DDR). Repair occurs within the chromatin landscape, with DDR sensors, mediators, signalling kinases and ubiquitin ligases rapidly recruited to the site of damage. Simultaneously, local chromatin modifications and remodelling take place, which also modulate local transcriptional activity. More complex chromatin dynamics are subsequently orchestrated within the three-dimensional nuclear space - persistent DSBs are actively relocated to specialized nuclear domains and chromatin compartments undergo spatial reorganization to facilitate efficient repair. In this Cell Science at a Glance article and the accompanying poster, we explore the interplay between local and global chromatin dynamics that coordinate DSB repair and preserve genome integrity within the context of a highly dynamic epigenome.
Esposito et al. (2026) studied this question.