miRNA-mediated cell-to-cell communications boost DNA repair during the radioadaptive response

The radioadaptive response (RAR) is a phenomenon in which a low, or priming, dose of ionizing radiation enhances cellular resistance to subsequent higher doses. We investigated whether RAR involves alterations in homologous recombination (HR), a high-fidelity DNA repair pathway. Using fibroblast models, we found that primed cells exhibit accelerated DNA end resection, an initial and essential HR step. This effect is mostly mediated by a bystander mechanism involving small extracellular vesicles (sEVs), as conditioned media fully replicated it. RNA profiling of sEVs identified miR-126-3p and miR-451a as key regulators of this response. Significantly, inhibiting miR-451a induced RAR in normally unresponsive cells. We further identified a miR-451a-p38-CCAR2 axis that promotes HR through suppression of CCAR2. Our findings delineate a novel microRNA-mediated, sEV-driven mechanism that regulates HR during RAR, with potential therapeutic implications.