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Double\u2010stranded DNA and RNA adopt different helical conformations, including the unusual Z\u2010conformation. Z\u2010DNA\/RNA is recognised by Z\u2010binding domains (ZBDs), which are present in proteins implicated in antiviral immunity. These include ZBP1 (also known as DAI or DLM\u20101), which induces necroptosis, an inflammatory form of cell death. Using reconstitution and knock\u2010in models, we report that mutation of key amino acids involved in Z\u2010DNA\/RNA binding in ZBP1's ZBDs prevented necroptosis upon infection with mouse cytomegalovirus. Induction of cell death was cell autonomous and required RNA synthesis but not viral DNA replication. Accordingly, ZBP1 directly bound to RNA via its ZBDs. Intact ZBP1\u2010ZBDs were also required for necroptosis triggered by ectopic expression of ZBP1 and caspase blockade, and ZBP1 cross\u2010linked to endogenous RNA. 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