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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 5423 |
| Tidsskrift | Nature Communications |
| Vol/bind | 15 |
| Antal sider | 14 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2024 |
| Udgivet eksternt | Ja |
Bibliografisk note
Funding Information:We thank Anne Letessier, Benjamin Pardo, Beno\u00EEt Le Tallec and Beno\u00EEt Miotto for their comments and suggestions on the manuscript. We thank the MRI imaging facility (Biocampus) for assistance with image acquisition and analysis. We thank Carl Mann (CEA/Saclay) for providing the IMR90-ER/RASV12 fibroblasts. H.T. has been supported by AIRC under the iCARE-2 fellowship program. Our project has received funding from AIRC and from the European Union\u2019s Horizon 2020 research and innovation program under the Marie Sk\u0142odowska-Curie grant agreement No 800924. Research carried by Y.L.L. is supported by the Fondation ARC pour la recherche sur le cancer (N\u00B0PJA 20191209522). Work in the Pasero lab is supported by grants from the Agence Nationale pour la Recherche (ANR), Institut National du Cancer (INCa), Ligue Nationale Contre le Cancer (\u00E9quipe labellis\u00E9e), Worldwide Cancer Research, Fondation ARC and Fondation MSDAVENIR.
Funding Information:
We thank Anne Letessier, Benjamin Pardo, Beno\u00EEt Le Tallec and Beno\u00EEt Miotto for their comments and suggestions on the manuscript. We thank the MRI imaging facility (Biocampus) for assistance with image acquisition and analysis. We thank Carl Mann (CEA/Saclay) for providing the IMR90-ER/RAS fibroblasts. H.T. has been supported by AIRC under the iCARE-2 fellowship program. Our project has received funding from AIRC and from the European Union\u2019s Horizon 2020 research and innovation program under the Marie Sk\u0142odowska-Curie grant agreement No 800924. Research carried by Y.L.L. is supported by the Fondation ARC pour la recherche sur le cancer (N\u00B0PJA 20191209522). Work in the Pasero lab is supported by grants from the Agence Nationale pour la Recherche (ANR), Institut National du Cancer (INCa), Ligue Nationale Contre le Cancer (\u00E9quipe labellis\u00E9e), Worldwide Cancer Research, Fondation ARC and Fondation MSDAVENIR.
Publisher Copyright:
© The Author(s) 2024.