Chen, Y, Norman, RX, Toufektchan, E, Luan, X, Shim, A, Rosenberg, H, Kovacs, MT, Nichols, A, Hickling, J, Cifani, P, Kentsis, A, Zhou, W, Maciejowski, J (March 2026) ER-tethering directs TREX1 penetration of a BAF-dependent barrier at micronuclei. Molecular Cell, 86 (6). 1099-1115.e10. ISSN 1097-2765
Abstract
Micronuclei are membrane-encapsulated nuclear aberrations that form following chromosome segregation errors. Micronuclear membrane collapse permits access of the pattern recognition receptor cGAS and its antagonist, the TREX1 exonuclease. TREX1 endoplasmic reticulum tethering is essential for invasion into ruptured micronuclei, but the mechanisms underlying this dependency are unknown. Here, we identify BAF as a key regulator of TREX1 activity at micronuclei. BAF accumulates at micronuclei following membrane collapse and augments TREX1 recruitment via interactions with LEM-domain proteins. Despite delayed entry, TREX1 exhibits enhanced micronuclear DNA degradation and independence from ER-tethering in BAF-deficient cells. Recombinant BAF inhibits TREX1-mediated DNA degradation in vitro via DNA-binding. BAF similarly outcompetes cGAS for micronuclear DNA and limits cGAS-dependent immune signaling. These findings reveal a BAF-dependent protective barrier to the diffusive entry of DNA-binding proteins into ruptured micronuclei that explains TREX1 ER-tethering requirements for suppressing innate immune responses in chromosomally unstable cells.
| Item Type: | Paper |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > organelles, types and functions > endoplasmic reticulum organs, tissues, organelles, cell types and functions > organelles, types and functions organs, tissues, organelles, cell types and functions |
| CSHL Authors: | |
| Communities: | CSHL labs > Cifani lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 19 March 2026 |
| Date Deposited: | 24 Mar 2026 18:23 |
| Last Modified: | 24 Mar 2026 18:23 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42109 |
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