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Interferons (IFN) are commonly induced following recognition of invading pathogens, including viral and bacterial infections. Disruptions to cellular homeostasis, including accumulation of DNA lesions, has also shown to drive IFN responses. Pattern recognition receptors (PRRs) identify nucleic acids derived either from pathogens or damaged host DNA to activate the STING pathway and induce IFNs. Because aberrant production of IFNs may drive immunopathologies, it is vital that the cell has negative regulators to control this response. Our lab has previously identified MEF2A as a novel negative regulator of type I IFN production and protects against excessive inflammation. Here we show that loss of MEF2A triggers the Replicative Stress Response (RSR) dependent on DDX41/STING to establish an inflammatory response. Additionally, type I IFN production following MEF2A deficiency is dependent on ATR kinase activity. Hence, this study is the first to connect the RSR with cGAS and IFI16-independent, DDX41-dependent activation of STING following depletion of MEF2A.