DNA damage at Lamina Associated Domains triggers nuclear envelope reorganization and chromatin detachment to prevent nuclear envelope blebbing and genome instability

The nuclear periphery anchors large, transcriptionally silent chromatin domains to the nuclear envelope and plays a central role in maintaining genome stability, acting as a dynamic hub for DNA repair. Nevertheless, how cells process DNA damage within lamina-associated domains (LADs), which reside in this environment, remains poorly understood, despite their relevance to nuclear architecture, aging, and senescence. Using systems for temporally controlled and spatially precise induction of double-strand breaks (DSBs) within LADs, we show that DNA damage triggers nuclear envelope remodeling, characterized by reduced lamin B1 and LBR levels and ATM-dependent mobilization of the LINC complex, which leads to the dynamic detachment of damaged LADs from the nuclear lamina. Persistent tethering of damaged LADs at the nuclear periphery delays the DNA damage response and repair, elevates genomic instability, and drives chromatin extrusion through nuclear blebs - directly linking failed repair to dysregulation of nuclear integrity. These findings reveal a protective mechanism in which ATM-driven LAD dynamics and envelope remodeling might relieve mechanical stress, facilitate repair, and safeguard both genome stability and nuclear architecture.