Fig. 8. Role of RS and cytosolic DNA sensing pathways in OIS.

a The DDR and cGAS-STING pathways are both required for the onset of OIS, but whether these pathways cooperate to induce senescence remains unclear. b Our data indicate that the nuclease MRE11 plays a central role in OIS by activating both the RS response and the cGAS-STING pathway via micronuclei formation. This function of MRE11 is counterbalanced by another nuclease, TREX1, which prevents activation of the cGAS-STING pathway by degrading cytosolic DNA. Remarkably, TREX1 inhibition or addition of IFN-β was sufficient to induce RS and senescence, even in the absence of RAS^V12 induction. Collectively, these data suggest that MRE11 activates a positive feedback loop that amplifies the RS response in OIS via activation of cytosolic DNA sensing.