Chromosomal instability in cancer results in the formation of nuclear aberrations termed micronuclei. Spontaneous loss of micronuclear envelope integrity exposes DNA to the cytoplasm, leading to chromosome fragmentation and innate immune activation. Despite connections to cancer genome evolution and anti-tumor immunity, the mechanisms underlying damage and immune sensing of micronuclear DNA are poorly understood. Here, we use a novel method for the purification of micronuclei and live-cell imaging to show that the ER-associated nuclease TREX1 inhibits cGAS sensing of micronuclei by stably associating with and degrading micronuclear DNA upon micronuclear envelope rupture.We identify a TREX1 mutation, previously associated with autoimmune disease, that untethers TREX1 from the ER, disrupts TREX1 localization to micronuclei, alleviates micronuclear DNA damage, and enhances cGAS recognition of micronuclei. Together, these results establish ER-directed resection of micronuclear DNA by TREX1 as a critical regulator of cytosolic DNA sensing in chromosomally unstable cells and provide a mechanistic basis for the importance of TREX1 ER-tethering in preventing autoimmunity.

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Separation of human sister chromatids involves the removal of DNA embracing cohesin ring complexes. Ring opening occurs by prophase-pathway-dependent phosphorylation and separase-mediated cleavage, with the former being antagonized at centromeres by Sgo1-dependent PP2A recruitment. Intriguingly, prophase pathway signaling and separase's proteolytic activity also bring about centriole disengagement, whereas Sgo1 is again counteracting this licensing step of later centrosome duplication. Here, we demonstrate that alternative splice variants of human Sgo1 specifically and exclusively localize and function either at centromeres or centrosomes. A small C-terminal peptide encoded by exon 9 of SGO1 (CTS for centrosomal targeting signal of human Sgo1) is necessary and sufficient to drive centrosomal localization and simultaneously abrogate centromeric association of corresponding Sgo1 isoforms. Cohesin is shown to be a target of the prophase pathway at centrosomes and protected by Sgo1-PP2A. Accordingly, premature centriole disengagement in response to Sgo1 depletion is suppressed by blocking ring opening of an engineered cohesin.

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Chromosomal instability in cancer results in the formation of nuclear aberrations termed micronuclei. Spontaneous loss of micronuclear envelope integrity exposes DNA to the cytoplasm, leading to chromosome fragmentation and innate immune activation. Despite connections to cancer genome evolution and anti-tumor immunity, the mechanisms underlying damage and immune sensing of micronuclear DNA are poorly understood. Here, we use a novel method for the purification of micronuclei and live-cell imaging to show that the ER-associated nuclease TREX1 inhibits cGAS sensing of micronuclei by stably associating with and degrading micronuclear DNA upon micronuclear envelope rupture.We identify a TREX1 mutation, previously associated with autoimmune disease, that untethers TREX1 from the ER, disrupts TREX1 localization to micronuclei, alleviates micronuclear DNA damage, and enhances cGAS recognition of micronuclei. Together, these results establish ER-directed resection of micronuclear DNA by TREX1 as a critical regulator of cytosolic DNA sensing in chromosomally unstable cells and provide a mechanistic basis for the importance of TREX1 ER-tethering in preventing autoimmunity. chromosomal instability | micronuclei | nuclear envelope | cGAS | TREX1