Pré-Publication, Document De Travail Année : 2023

Regulation of oncogene-induced senescence by the MRE11 and TREX1 nucleases

Résumé

Oncogene-induced senescence (OIS) is a tumor-suppressive mechanism that arrests cell proliferation in response to oncogene-induced replication stress (RS). OIS also depends on the cGAS-STING pathway, which detects cytosolic DNA and promotes the expression of type I interferons (IFN) and pro-inflammatory cytokines. Whether and how the RS and IFN responses cooperate to promote OIS is currently unknown. Here, we show that the MRE11 nuclease promotes OIS in immortalized human fibroblasts overexpressing the H-RAS V12 oncogene both by slowing replication forks and by activating the cGAS-STING pathway in response to RS. Interestingly, overexpression of TREX1, the major nuclease degrading cytosolic DNA, prevented RAS-induced senescence. In contrast, overexpression of a dominant negative mutant of TREX1 was sufficient to induce senescence in human fibroblasts, even in the absence of H-RAS V12 induction. Collectively, these data suggest that the RS and IFN responses in OIS are functionally linked through a process involving the nucleases MRE11 and TREX1.

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hal-04315770 , version 1 (30-11-2023)

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Hervé Técher, Diyavarshini Gopaul, Jonathan Heuzé, Baptiste Leray, Audrey Vernet, et al.. Regulation of oncogene-induced senescence by the MRE11 and TREX1 nucleases. 2023. ⟨hal-04315770⟩
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