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2.  Conflicts Targeting Epigenetic Systems and Their Resolution by Cell Death: Novel Concepts for Methyl-Specific and Other Restriction Systems 
Epigenetic modification of genomic DNA by methylation is important for defining the epigenome and the transcriptome in eukaryotes as well as in prokaryotes. In prokaryotes, the DNA methyltransferase genes often vary, are mobile, and are paired with the gene for a restriction enzyme. Decrease in a certain epigenetic methylation may lead to chromosome cleavage by the partner restriction enzyme, leading to eventual cell death. Thus, the pairing of a DNA methyltransferase and a restriction enzyme forces an epigenetic state to be maintained within the genome. Although restriction enzymes were originally discovered for their ability to attack invading DNAs, it may be understood because such DNAs show deviation from this epigenetic status. DNAs with epigenetic methylation, by a methyltransferase linked or unlinked with a restriction enzyme, can also be the target of DNases, such as McrBC of Escherichia coli, which was discovered because of its methyl-specific restriction. McrBC responds to specific genome methylation systems by killing the host bacterial cell through chromosome cleavage. Evolutionary and genomic analysis of McrBC homologues revealed their mobility and wide distribution in prokaryotes similar to restriction–modification systems. These findings support the hypothesis that this family of methyl-specific DNases evolved as mobile elements competing with specific genome methylation systems through host killing. These restriction systems clearly demonstrate the presence of conflicts between epigenetic systems.
PMCID: PMC2993543  PMID: 21059708
intragenomic conflict; programmed cell death; epigenetic DNA methylation; restriction–modification system; McrBC
3.  Cell death upon epigenetic genome methylation: a novel function of methyl-specific deoxyribonucleases 
Genome Biology  2008;9(11):R163.
The McrBC methyl-specific deoxyribonuclease from Escherichia coli can respond to genome methylation by host killing.
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.
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 became 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 chromosome processing and, together with the SOS response, reduce lethality. Our evolutionary/genomic analyses of McrBC homologs revealed: a wide distribution in Prokaryota; frequent distant horizontal transfer and linkage with mobility-related genes; and 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.
Our experiments indicate McrBC can respond to genome methylation systems by host killing. Combined with our evolutionary/genomic analyses, they support our hypothesis that 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.
PMCID: PMC2614495  PMID: 19025584

Results 1-3 (3)