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- Title
MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling.
- Authors
Técher, Hervé; Gopaul, Diyavarshini; Heuzé, Jonathan; Bouzalmad, Nail; Leray, Baptiste; Vernet, Audrey; Mettling, Clément; Moreaux, Jérôme; Pasero, Philippe; Lin, Yea-Lih
- Abstract
Oncogene-induced senescence (OIS) arrests cell proliferation in response to replication stress (RS) induced by oncogenes. OIS depends on the DNA damage response (DDR), but also on the cGAS-STING pathway, which detects cytosolic DNA and induces type I interferons (IFNs). Whether and how RS and IFN responses cooperate to promote OIS remains unknown. Here, we show that the induction of OIS by the H-RASV12 oncogene in immortalized human fibroblasts depends on the MRE11 nuclease. Indeed, treatment with the MRE11 inhibitor Mirin prevented RS, micronuclei formation and IFN response induced by RASV12. Overexpression of the cytosolic nuclease TREX1 also prevented OIS. Conversely, overexpression of a dominant negative mutant of TREX1 or treatment with IFN-β was sufficient to induce RS and DNA damage, independent of RASV12 induction. These data suggest that the IFN response acts as a positive feedback loop to amplify DDR in OIS through a process regulated by MRE11 and TREX1. Oncogene-induced senescence is a key tumor suppressor mechanism. Here, the authors show that replication stress induced by the RASV12 oncogene activates the cGAS-STING pathway, which in turn acts as a positive feedback loop to promote senescence.
- Subjects
GERMANY (East); DNA repair; TYPE I interferons; INTERFERON receptors; INTERFERONS; DNA damage
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49740-w