Cell death upon epigenetic genome methylation: a novel function of methyl-specific deoxyribonucleases

Background Alteration in epigenetic methylation can affect gene expression and other processes. In Prokaryota, DNA methyltransferase genes frequently move between genomes and present a potential threat. A methyl-specific deoxyribonuclease, McrBC, of Escherichia coli cuts invading methylated DNAs. Here we examined whether McrBC competes with genome methylation systems through host killing by chromosome cleavage. Results McrBC inhibited the establishment of a plasmid carrying a PvuII methyltransferase gene but lacking its recognition sites, likely through the lethal cleavage of chromosomes that become methylated. Indeed, its phage-mediated transfer caused McrBC-dependent chromosome cleavage. Its induction led to cell death accompanied by chromosome methylation, cleavage and degradation. RecA/RecBCD functions affect the chromosome processing and, together with SOS response, reduce the lethality. Our evolutionary/genomic analyses of mcrBC homologs revealed (i) wide distribution in Prokaryota, (ii) frequent distant horizontal transfer and linkage with mobility-related genes, (iii) diversification in the DNA binding domain. In these features, McrBCs resemble Type II restriction-modification systems, which behave as selfish mobile elements maintaining their frequency by host killing. McrBCs are frequently found linked with a methyltransferase homolog, which suggests a functional association. Conclusions Our experiments indicate McrBC can respond to genome methylation systems by host killing. Combined with our evolutionary/genomic analyses, they support our hypothesis McrBCs have evolved as mobile elements competing with specific genome methylation systems through host killing. To our knowledge, this represents the first report of a defense system against epigenetic systems through cell death.