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

DNA damage at Lamina Associated Domains triggers nuclear envelope reorganization and chromatin detachment to prevent nuclear envelope blebbing and genome instability | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article DNA damage at Lamina Associated Domains triggers nuclear envelope reorganization and chromatin detachment to prevent nuclear envelope blebbing and genome instability Evi Soutoglou, Diana Rubio-Contreras, Sylvain Audibert, Ruxandra A. Lambuta, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7742980/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version 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. 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. Biological sciences/Genetics/Epigenetics Biological sciences/Molecular biology/Epigenetics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files RubioAudibertSupplementaryinformation.pdf Supplementary information Extendeddatamovie4.avi ATM associated with fig 6A Extendeddatamovie5.avi ATM associated with fig 6B Extendeddatamovie2.avi DMSO associated with fig 6B Extendeddatamovie3.avi DMSO associated with fig 6C Extendeddatamovie1.avi DMSO associated with fig 6A Extendeddatamovie6.avi ATM associated with fig 6C Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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