Cyclic oligonucleotide-based anti-phage signaling system (CBASS)-associated NucC nuclease kills phage-infected cells through genome destruction. It is allosterically activated by a cyclic triadenylate (cA3) second messenger that is synthesized by CBASS upon infection. NucC is related to restriction endonucleases but it adopts a homotrimeric structure. Binding of cA3 causes two NucC homotrimers to assemble into a homohexamer, which brings together a pair of active sites to activate DNA cleavage. NucC has also been integrated into type III CRISPR/Cas systems as an accessory nuclease.