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

Abstract

The Dam methylase of gamma-proteobacteria and the CcrM methylase of alpha-proteobacteria catalyze an identical reaction (methylation of adenosine moieties using S-adenosyl-methionine as 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. Formation of 6-methyladenine lowers 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 only partially understood. Especially intriguing is the evidence that Dam methylation regulates virulence genes in E. coli, Salmonella, and Yersinia at the postranscriptional level.