Article Dans Une Revue Nature Communications Année : 2024

MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling

Résumé

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-RAS V12 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 RAS V12 . 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 RAS V12 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.

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hal-04748159 , version 1 (21-11-2024)

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Hervé Técher, Diyavarshini Gopaul, Jonathan Heuzé, Nail Bouzalmad, Baptiste Leray, et al.. MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling. Nature Communications, 2024, 15 (1), pp.5423. ⟨10.1038/s41467-024-49740-w⟩. ⟨hal-04748159⟩
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