ER-directed TREX1 limits cGAS activation at micronuclei

Summary Micronuclei are aberrant nuclear compartments that can form as a result of chromosome mis-segregation. Frequent loss micronuclear envelope integrity exposes DNA to the cytoplasm, leading fragmentation and immune activation. Here, we use micronuclei purification show endoplasmic reticulum (ER)-associated nuclease TREX1 inhibits cGAS activation at by degrading upon rupture. We demonstrate ER accesses ruptured plays critical role in enabling nucleolytic attack. TREX1 mutations, previously implicated disease, untether from ER, disrupt localization micronuclei, diminish damage, enhance These results establish ER-directed resection regulator cytosolic sensing chromosomally unstable cells provide mechanistic basis for importance tethering preventing autoimmunity.