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  • Review Article
  • Published:

N6-methyl-adenine: an epigenetic signal for DNA–protein interactions

Nature Reviews Microbiology volume 4, pages 183–192 (2006)Cite this article

Key Points

  • N6-methyl-adenine is a common DNA modification in bacterial genomes, which is catalysed by two classes of DNA adenine methyltransferases: those associated with restriction–modification (R–M) systems and 'solitary' methyltransferases that do not have a restriction-enzyme companion.

  • R–M systems protect bacteria from the invasion of foreign DNA (for example, phages). Each R–M system is made up of a restriction enzyme and a modification enzyme, which both recognize the same DNA target. Some modification enzymes are DNA adenine methyltransferases, whereas others are DNA cytosine methyltransferases.

  • In γ-proteobacteria, methylation of the adenine moiety at GATC sites by the Dam methylase provides signals for chromosome replication, nucleoid organization and segregation, mismatch repair, transposition of insertion elements, phase variation, bacterial conjugation and packaging of phage DNA. Furthermore, Dam methylation is required for virulence in Salmonella, Haemophilus, Yersinia and Vibrio species.

  • In uropathogenic Escherichia coli, phase variation in Pap fimbriae is regulated at the transcriptional level by Dam methylation and the leucine-responsive regulatory protein (Lrp). Synthesis of Prf, S, Afa, K88 and CS31a fimbriae is also regulated by Dam methylation and Lrp. In turn, phase variation in the E. coli Agn43 antigen is regulated by Dam and OxyR.

  • In Salmonella, Dam methylation regulates the expression of genes involved in invasion of epithelial cells (SPI-1 genes), synthesis of fimbrial adhesins (Pef and Std), envelope proteins (Braun lipoprotein), flagella and chemotaxis. Also, Dam methylation is required for bile resistance.

  • Dam methylation regulates conjugal transfer of the Salmonella virulence plasmid and other F-like plasmids.

  • In Caulobacter and other α-proteobacteria, methylation of the adenine moiety at GANTC sites by the CcrM methylase regulates the cell cycle and is essential for viability. Lack of CcrM methylation attenuates virulence in Brucella.

  • DNA adenine methylation is found in the genomes of certain protists and fungi, and might exist in other eukaryotes.

Abstract

N6-methyl-adenine is found in the genomes of bacteria, archaea, protists and fungi. Most bacterial DNA adenine methyltransferases are part of restriction–modification systems. Certain groups of Proteobacteria also harbour solitary DNA adenine methyltransferases that provide signals for DNA–protein interactions. In γ-proteobacteria, Dam methylation regulates chromosome replication, nucleoid segregation, DNA repair, transposition of insertion elements and transcription of specific genes. In Salmonella, Haemophilus, Yersinia and Vibrio species and in pathogenic Escherichia coli, Dam methylation is required for virulence. In α-proteobacteria, CcrM methylation regulates the cell cycle in Caulobacter, Rhizobium and Agrobacterium, and has a role in Brucella abortus infection.

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Figure 1: Overview of the roles of N6-methyl-adenine in enteric bacteria.
Figure 2: Dam-directed mismatch repair.
Figure 3: Model for switching from phase OFF to phase ON in the pap operon of uropathogenic Escherichia coli.
Figure 4: Model for regulation of agn43 transcription.
Figure 5: Model for regulation of traJ transcription in the Salmonella virulence plasmid.
Figure 6: Regulation of the Caulobacter cell cycle.

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Acknowledgements

Work in our laboratories is supported by grants from the Lejeune Foundation (to D.W.), and from the Spanish Ministry of Education and the European Regional Fund (to J.C.). We are grateful to D. Low and F. Antequera for helpful discussions. D.W. thanks A. L. Benabid and F. Berger for their support.

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Authors and Affiliations

  1. INSERM U318, CHU Michallon, Université Joseph Fourier, Grenoble, 38043, France

    Didier Wion

  2. Departamento de Genética, Universidad de Sevilla, Apartado 1095, Seville, 41080, Spain

    Josep Casadesús

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  1. Didier Wion
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Correspondence to Didier Wion.

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DATABASES

Entrez Genome

Mu

P1

PSLT

Entrez Genome Project

Agrobacterium tumefaciens

Brucella abortus

Caulobacter crescentus

Chlamydomonas reinhardtii

Escherichia coli

Haemophilus influenzae

Pasteurella multocida

Salmonella enterica

Shigella flexneri

Sinorhizobium meliloti

Vibrio cholerae

Yersinia enterocolitica

Yersinia pseudotuberculosis

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Glossary

Restriction–modification (R–M) system

Bacterial mechanism of defence against invasion by foreign DNA (for example, viruses). They are composed of genes that encode a restriction enzyme and a modification methylase.

Distributive enzyme

Enzyme that dissociates from its substrate after one round of catalysis.

Processive enzyme

Enzyme that performs multiple cycles of catalysis without dissociating from its substrate.

Transition mutation

A nucleotide substitution that changes a purine to a purine (A↔G) or a pyrimidine to a pymiridine (C↔T).

Leucine-responsive regulatory protein

Global regulator of the bacterial cell that regulates gene expression in response to exogenous leucine and other metabolic signals.

Adhesin

Bacterial surface protein that facilitates adhesion to host tissues.

Redox-sensitive regulator

Protein that can exist in two different states in response to the redox potential of the cell.

Conjugal transfer

Transfer of bacterial DNA on cell-to-cell contact.

F sex factor

Plasmid that is present in certain Escherichia coli strains that can transfer chromosomal genes, which led to the discovery of bacterial conjugation.

Translocase

A protein involved in the translocation of proteins across membranes, and in the integration of proteins into the cytoplasmic membrane.

Salmonella pathogenicity island I

(SPI-1). Gene cluster of ∼40 kb, located on centisome 63 in the Salmonella chromosome. The products of SPI-1 are necessary for invasion of epithelial cells.

M (microfold) cell

Cell type located in the Peyer's patches of the small intestine. M cells are involved in antigen transport and interact with Salmonella and other bacterial pathogens.

Lysogen

Bacterial cell that carries a viral genome in a non-infectious, repressed state.

Rolling-circle replication

Mode of DNA replication that uses a circular DNA molecule as a template to produce concatemers of linear DNA molecules.

Headful mechanism

Introduction of DNA into a bacteriophage capsid in such a way that the length of the packaged DNA molecule is determined by the size of the capsid.

Theta replication

Mode of DNA replication that uses a circular DNA molecule as a template to produce two circular DNA molecules.

Genomic imprinting

Epigenetic mechanism in diploid organisms by which only one allele (maternal or paternal) is expressed.

X-chromosome inactivation

Epigenetic silencing of most genes in one of the two X chromosomes in somatic cells of mammalian females.

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Wion, D., Casadesús, J. N6-methyl-adenine: an epigenetic signal for DNA–protein interactions. Nat Rev Microbiol 4, 183–192 (2006). https://doi.org/10.1038/nrmicro1350

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