Roles of DNA adenine methylation in host-pathogen interactions: mismatch repair, transcriptional regulation, and more

Abstract

The DNA adenine methyltransferase (Dam methylase) of Gammaproteobacteria and the cell cycle-regulated methyltransferase (CcrM) methylase of Alphaproteobacteria catalyze an identical reaction (methylation of adenosine moieties using S-adenosyl-methionine as a methyl donor) at similar DNA targets (GATC and GANTC, respectively). Dam and CcrM are of independent evolutionary origin. Each may have evolved from an ancestral restriction-modification system that lost its restriction component, leaving an 'orphan' methylase devoted solely to epigenetic genome modification. The formation of 6-methyladenine reduces the thermodynamic stability of DNA and changes DNA curvature. As a consequence, the methylation state of specific adenosine moieties can affect DNA-protein interactions. Well-known examples include binding of the replication initiation complex to the methylated oriC, recognition of hemimethylated GATCs in newly replicated DNA by the MutHLS mismatch repair complex, and discrimination of methylation states in promoters and regulatory DNA motifs by RNA polymerase and transcription factors. In recent years, Dam and CcrM have been shown to play roles in host-pathogen interactions. These roles are diverse and have only partially been understood. Especially intriguing is the evidence that Dam methylation regulates virulence genes in Escherichia coli, Salmonella, and Yersinia at the posttranscriptional level.

Figure 1

States of GATC site methylation in gamma-proteobacteria. DNA replication generates hemimethylated GATC sites, usually short-lived since Dam methylation occurs shortly after synthesis of the daughter DNA strand. At certain GATC sites, however, the default methylation-hemimethylation cycle associated with DNA replication can be skewed by binding of proteins that prevent DNA methylase activity. Such binding can merely delay methylation or prevent it beyond cell division, thereby permitting daughter cells to inherit the hemimethylated state if methylation hindrance persists. Replication of hemimethylated GATC sites produces unmethylated DNA, generating DNA methylation patterns like those occurring in eukaryotic cells.

Figure 2

Overview of the roles of 6-meA in enteric bacteria. When known, the methylation-sensitive DNA-binding proteins involved in each process are also indicated.

Figure 3

Cell functions under Dam methylation control in bacterial pathogens.