ER-Directed TREX1 Limits cGAS Recognition of Micronuclei
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TLDR
A novel method for the purification of micronuclei and live-cell imaging is used to show that the ER-associated nuclease TREX1 inhibits cGAS sensing of micronsuclei by stably associating with and degrading micronuclear DNA upon micronsuclear envelope rupture, establishing ER-directed resection of micRONuclear DNA by TREX 1 as a critical regulator of cytosolic DNA sensing in chromosomally unstable cells.Abstract:
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.read more
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Journal ArticleDOI
Genome instability from nuclear catastrophe and DNA damage.
Anna E Mammel,Emily M. Hatch +1 more
TL;DR: In this article, a review discusses three major circumstances that promote nuclear membrane rupture, nuclear deformation, chromatin bridges, and micronucleation, and how each of these nuclear catastrophes results in DNA damage, highlighting recent studies that demonstrate a single chromosome missegregation can initiate a cascade of events that lead to accumulating damage and even multiple rounds of chromothripsis.
Journal ArticleDOI
Genome instability from nuclear catastrophe and DNA damage
TL;DR: In this paper , a review discusses three major circumstances that promote nuclear membrane rupture, nuclear deformation, chromatin bridges, and micronucleation, and how each of these nuclear catastrophes results in DNA damage.
Posted ContentDOI
Chromosome length and gene density contribute to micronuclear membrane stability
TL;DR: In this article, the authors demonstrate that chromosome length and micronuclei size strongly correlate with lamin B1 and nuclear pore density in intact micronucli, and propose an unknown factor linked to gene density that inhibits the appearance of nuclear lamina gaps and delays membrane rupture until late in the cell cycle.