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

Hervé Técher, Diyavarshini Gopaul, Jonathan Heuzé, Nail Bouzalmad, Baptiste Leray, Audrey Vernet, Clément Mettling, Jérôme Moreaux, Philippe Pasero () and Yea-Lih Lin ()
Additional contact information
Hervé Técher: Equipe Labellisée Ligue contre le Cancer
Diyavarshini Gopaul: Equipe Labellisée Ligue contre le Cancer
Jonathan Heuzé: Equipe Labellisée Ligue contre le Cancer
Nail Bouzalmad: Equipe Labellisée Ligue contre le Cancer
Baptiste Leray: Equipe Labellisée Ligue contre le Cancer
Audrey Vernet: Equipe Labellisée Ligue contre le Cancer
Clément Mettling: CNRS
Jérôme Moreaux: CNRS
Philippe Pasero: Equipe Labellisée Ligue contre le Cancer
Yea-Lih Lin: Equipe Labellisée Ligue contre le Cancer

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-49740-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49740-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-49740-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().