Conflicts Targeting Epigenetic Systems and Their Resolution by Cell Death: Novel Concepts for Methyl-Specific and Other Restriction Systems

Abstract

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.

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

“…Since HGT between prokaryotic genomes is common, and the DNA MTase genes are known to undergo rampant transfer among organisms (41,170), untimely methylation represents a possible threat to the methylation pattern of the host genomes. Recently, Ishikawa et al dealt with this topic in detail and discussed various ways by which the epigenetic methylation of a genome is protected (171). The underlying mechanisms in the resolution of conflicts between different methylation systems in such a scenario have been reviewed (171).…”

“…Recently, Ishikawa et al dealt with this topic in detail and discussed various ways by which the epigenetic methylation of a genome is protected (171). The underlying mechanisms in the resolution of conflicts between different methylation systems in such a scenario have been reviewed (171). According to this model, the function of R-M systems is to impose a particular methylation pattern in the host.…”

Bacterial Genome Instability

“…Essentially, an RM system encodes a restriction endonuclease and its cognate modification activity, most often a methyltransferase (242)(243)(244)(245)(246)(247)(248)(249)(250). When several proteins are needed to perform these activities, their genes are usually located together on the bacterial chromosome, a virus, or a mobile element.…”

“…Fourth, they can increase bacterial diversity and phase and antigenic variation by inducing genomic rearrangement and homologous recombination during break repair or with incoming foreign DNA (restriction of the invading DNA might help separate beneficial and deleterious mutations) (243,244). Fifth, they have been hypothesized to monitor the epigenetic DNA methylation level of their host in order to eliminate cells with unusual levels of methylation (248).…”

Defense Islands in Bacterial and Archaeal Genomes and Prediction of Novel Defense Systems

“…Thus, the Abi systems are effectively a variant of the TA systems (20). It should be noted that defense systems that employ the self-nonself discrimination mechanism have the potential to evolve into systems causing cell suicide or dormancy, as shown for RM systems (22,33).…”