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MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling
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MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling
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Journal Article
MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling
2024
Overview
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.
Oncogene-induced senescence is a key tumor suppressor mechanism. Here, the authors show that replication stress induced by the RASV12 oncogene activates the cGAS-STING pathway, which in turn acts as a positive feedback loop to promote senescence.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/89
/ 14
/ 14/1
/ 631/67
/ Cellular Senescence - genetics
/ Damage
/ DNA
/ Exodeoxyribonucleases - genetics
/ Exodeoxyribonucleases - metabolism
/ Feedback
/ Humanities and Social Sciences
/ Humans
/ Interferon-beta - metabolism
/ MRE11 Homologue Protein - genetics
/ MRE11 Homologue Protein - metabolism
/ Nuclease
/ Phosphoproteins - metabolism
/ Science
