LAUSR

Abstract The arms race between phages and bacteria is dynamic and ongoing, with both continuously acquiring new strategies to outcompete each other during co-evolution. Here, we report bacteriophage T4 exonuclease DexA and an uncharacterized Escherichia coli exonuclease as a rare pair of attack and defense duo arising from the same mechanism. DexA, highly conserved among phages, has two well-characterized biological roles: host DNA scavenging and intron homing. Unmodified DNA is the substrate during host DNA scavenging, whereas cleavage of 5hmC (5-hydroxymethylcytosine)-modified phage DNA is required for intron homing. We reveal a temperature-driven quaternary fold switch between DexA dimer and tetramer that facilitates cleavage of distinct DNA forms, namely 5hmC-modified phage DNA and unmodified host DNA. As a countermeasure, bacteria produce DexA variants for defense against phage that only targets 5hmC-modified DNA. Thus, both phages and bacteria compete using HmC-Recognizing EXonuclease strategies (designated as HREX).