biostudies-literatureMacDonald KMGouvernement du Canada | Natural Sciences and Engineering Research Council of CanadaJP Bickell foundation Princess Margaret Cancer Foundation Princess Margaret Cancer Centre Ontario Ministry of HealthNCI NIH HHSNIH HHSNIGMS NIH HHSGouvernement du Canada | Canadian Institutes of Health Research556https://www.ebi.ac.uk/biostudies/studies/S-EPMC9894866biostudies-literatureUnknown14(1)Micronuclei (MN) are cytosolic bodies that sequester acentric fragments or mis-segregated chromosomes from the primary nucleus. Spontaneous rupture of the MN envelope allows recognition by the viral receptor cyclic GMP-AMP synthase (cGAS), initiating interferon signaling downstream of DNA damage. Here, we demonstrate that MN rupture is permissive but not sufficient for cGAS localization. Chromatin characteristics such as histone 3, lysine 79 dimethylation (H3K79me2) are present in the nucleus before DNA damage, retained in ruptured MN, and regulate cGAS recruitment. cGAS is further responsive to dynamic intra-MN processes occurring prior to rupture, including transcription. MN chromatin tethering via the nucleosome acidic patch is necessary for cGAS-dependent interferon signaling. Our dataNature communicationsAntecedent chromatin organization determines cGAS recruitment to ruptured micronuclei.PMC9894866RGPIN 2019 0481S10 OD025194PJT 165926P30 CA060553P41 GM108569Tageldein MMArrowsmith CHHarding SMNicholson-Puthenveedu SKhasnis SMacDonald KMfalseAntecedent chromatin organization determines cGAS recruitment to ruptured micronuclei.Micronuclei (MN) are cytosolic bodies that sequester acentric fragments or mis-segregated chromosomes from the primary nucleus. Spontaneous rupture of the MN envelope allows recognition by the viral receptor cyclic GMP-AMP synthase (cGAS), initiating interferon signaling downstream of DNA damage. Here, we demonstrate that MN rupture is permissive but not sufficient for cGAS localization. Chromatin characteristics such as histone 3, lysine 79 dimethylation (H3K79me2) are present in the nucleus before DNA damage, retained in ruptured MN, and regulate cGAS recruitment. cGAS is further responsive to dynamic intra-MN processes occurring prior to rupture, including transcription. MN chromatin tethering via the nucleosome acidic patch is necessary for cGAS-dependent interferon signaling. Our data2023-01-01T00:00:00Z2023 Feb2026-03-17T15:58:52.581Z2025-04-06T02:21:49.723ZS-EPMC98948663673252710.1038/s41467-023-36195-8