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

Autor: Técher H; Institut de Génétique Humaine, University of Montpellier, CNRS, Equipe Labellisée Ligue contre le Cancer, Montpellier, France.; Institute for Research on Cancer and Aging of Nice (IRCAN), Université Côte d'Azur, CNRS UMR7284 - INSERM U1081, Nice, France., Gopaul D; Institut de Génétique Humaine, University of Montpellier, CNRS, Equipe Labellisée Ligue contre le Cancer, Montpellier, France.; Biotech Research and Innovation Centre, University of Copenhagen, 2200 N, Copenhagen, Denmark., Heuzé J; Institut de Génétique Humaine, University of Montpellier, CNRS, Equipe Labellisée Ligue contre le Cancer, Montpellier, France., Bouzalmad N; Institut de Génétique Humaine, University of Montpellier, CNRS, Equipe Labellisée Ligue contre le Cancer, Montpellier, France., Leray B; Institut de Génétique Humaine, University of Montpellier, CNRS, Equipe Labellisée Ligue contre le Cancer, Montpellier, France., Vernet A; Institut de Génétique Humaine, University of Montpellier, CNRS, Equipe Labellisée Ligue contre le Cancer, Montpellier, France., Mettling C; Institut de Génétique Humaine, University of Montpellier, CNRS, Montpellier, France., Moreaux J; Institut de Génétique Humaine, University of Montpellier, CNRS, Montpellier, France.; Department of Biological Hematology, CHU Montpellier, Montpellier, France.; University of Montpellier, UFR Medicine, Montpellier, France., Pasero P; Institut de Génétique Humaine, University of Montpellier, CNRS, Equipe Labellisée Ligue contre le Cancer, Montpellier, France. philippe.pasero@igh.cnrs.fr., Lin YL; Institut de Génétique Humaine, University of Montpellier, CNRS, Equipe Labellisée Ligue contre le Cancer, Montpellier, France. yea-lih.lin@igh.cnrs.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jun 26; Vol. 15 (1), pp. 5423. Date of Electronic Publication: 2024 Jun 26.
DOI: 10.1038/s41467-024-49740-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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