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

Abstract

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. By employing systems for temporally controlled and spatially precise induction of DNA double-strand breaks (DSBs) within LADs, we show that DSBs within LADs trigger remodeling of the nuclear lamina and the dynamic detachment of damaged LADs from the nuclear envelope, resulting in their relocalization to the nuclear interior. This process is orchestrated by the ATM/{gamma}H2AX/MDC1/RNF168/53BP1 axis and requires the linker of nucleoskeleton and cytoskeleton (LINC) complex and cytoskeletal components while leaving DNA repair pathway choice unchanged. 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 nuclear envelope remodeling might relieve mechanical stress, facilitate repair, and safeguard both genome stability and nuclear architecture.