Abstract
The mammalian genome is hierarchically structured to maintain accessibility and flexibility for essential nuclear processes such as transcription and DNA repair. A recent study using high-throughput 3D genome mapping reveals that nucleotide excision repair triggers large-scale chromatin rearrangements, reinforcing topologically associating domains and chromatin compartments. Notably, similar principles of chromatin stabilization are observed during double-strand break repair, consistent with the notion that chromatin restructuring may be an active and conserved DNA repair strategy rather than a passive consequence of damage. The observed stabilization is postulated to optimize repair efficiency by reducing the search space for damage, enhancing DNA accessibility at damage sites, increasing local concentrations of repair factors, and preventing aberrant chromosomal rearrangements. By synthesizing emerging evidence on nucleotide excision repair-driven chromatin dynamics and its parallels with double-strand break repair, this review examines how genome architecture actively shapes the DNA damage response and highlights broader implications for genetic diseases and therapeutic strategies.