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 data suggest that both damage-antecedent nuclear chromatin status and MN-contained chromatin organizational changes dictate cGAS recruitment and the magnitude of the cGAS-driven interferon cascade. Our work defines MN as integrative signaling hubs for the cellular response to genotoxic stress.

微核 (MN) 是一种胞质体，可隔离来自原核的无着丝粒片段或错误分离的染色体。 MN 包膜的自发破裂允许病毒受体环 GMP-AMP 合酶 (cGAS) 识别，启动 DNA 损伤下游的干扰素信号传导。在这里，我们证明 MN 破裂是允许的，但不足以用于 cGAS 定位。组蛋白 3、赖氨酸 79 二甲基化 (H3K79me2) 等染色质特征在 DNA 损伤之前存在于细胞核中，保留在破裂的 MN 中，并调节 cGAS 募集。 cGAS 进一步响应破裂前发生的动态 MN 内过程，包括转录。通过核小体酸性斑块进行的 MN 染色质束缚对于 cGAS 依赖性干扰素信号传导是必需的。我们的数据表明，损伤前核染色质状态和含有 MN 的染色质组织变化决定了 cGAS 募集和 cGAS 驱动的干扰素级联的大小。我们的工作将 MN 定义为细胞对基因毒性应激反应的综合信号中心。