Bacteria sense virus-induced genome degradation via methylated mononucleotides

Phages often degrade the genome of their bacterial host to individual nucleotides. In this work, we describe Metis, a bacterial defense system that directly senses phage-mediated host genome degradation. Metis aborts phage infection once it detects the modified mononucleotide N 6 -methyl-deoxyadenosine monophosphate (m 6 dAMP). As methylation of deoxyadenosines usually occurs on the DNA polymer, accumulation of m 6 dAMP signals that the host genome has been degraded. In type I Metis, sensing of m 6 dAMP activates a nicotinamide adenine dinucleotide (NAD + ) diphosphatase, leading to NAD + depletion and cessation of the infection process, whereas the effector in type II Metis is a membrane-spanning protein whose toxicity is triggered in response to the modified mononucleotide. We further show that Metis defense depends on endogenous DNA methylases and that phages can escape Metis through mutations that inactivate host genome degradation.