Bacterial restriction-modification systems: mechanisms of defense against phage infection

Bacteria have evolved various defense mechanisms against bacteriophage invasion, driven by a long-term evolutionary arms race. Among them, restriction-modification (R-M) systems, which protect bacteria by DNA restriction and modification, are prominent. R-M systems are categorized based on their DNA methylation mechanisms, restriction activities, and cofactor dependencies. Here, we review the molecular basis of R-M systems and the diverse strategies used by bacteriophages to evade these defenses. Furthermore, we highlight the co-evolutionary dynamics between R-M systems and phage countermeasures, providing insights into new approaches to combat bacterial resistance and pathogenicity. Beyond their defensive roles, the multifunctionality of R-M systems in broader biological and biotechnological contexts is also discussed.

• Publication year

  2025

• Venue

  Biophysics Reports

• Publication date

  2025-10-31

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.52601/bpr.2025.240070PMID 41229888PMCID 12602166
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• CARD domains mediate anti-phage defence in bacterial gasdermin systems

  2025cited by this paper
• Phage-triggered reverse transcription assembles a toxic repetitive gene from a non-coding RNA

  2024cited by this paper
• Landscape of New Nuclease-Containing Antiphage Systems in Escherichia coli and the Counterdefense Roles of Bacteriophage T4 Genome Modifications

  2023cited by this paper
• Broadness and specificity: ArdB, ArdA, and Ocr against various restriction-modification systems

  2023cited by this paper
• The DNA Phosphorothioation Restriction-Modification System Influences the Antimicrobial Resistance of Pathogenic Bacteria

  2023cited by this paper
• The Battle between Bacteria and Bacteriophages: A Conundrum to Their Immune System

  2023cited by this paper
• Anti-Restriction Activity of ArdB Protein against EcoAI Endonuclease

  2023cited by this paper
• The extremophile Picrophilus torridus carries a DNA adenine methylase M.PtoI that is part of a Type I restriction-modification system

  2023cited by this paper
• Structures, activity and mechanism of the Type IIS restriction endonuclease PaqCI

  2023cited by this paper
• Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease

  2022cited by this paper
• REBASE: a database for DNA restriction and modification: enzymes, genes and genomes

  2022cited by this paper
• The functional coupling between restriction and DNA phosphorothioate modification systems underlying the DndFGH restriction complex

  2022cited by this paper
• Restriction Enzymes.

  2021cited by this paper
• SAMase of Bacteriophage T3 Inactivates Escherichia coli’s Methionine S-Adenosyltransferase by Forming Heteropolymers

  2021cited by this paper
• Structural and functional diversity among Type III restriction-modification systems that confer host DNA protection via methylation of the N4 atom of cytosine

  2021cited by this paper
• A Type I Restriction Modification System Influences Genomic Evolution Driven by Horizontal Gene Transfer in Paenibacillus polymyxa

  2021cited by this paper
• Bacterial N4-methylcytosine as an epigenetic mark in eukaryotic DNA

  2021cited by this paper
• Characterization of the Type I Restriction Modification System Broadly Conserved among Group A Streptococci

  2021cited by this paper
• Structural and functional evidence of bacterial antiphage protection by Thoeris defense system via NAD+ degradation

  2020cited by this paper
• SspABCD–SspE is a phosphorothioation-sensing bacterial defence system with broad anti-phage activities

  2020cited by this paper
• Structural asymmetry governs the assembly and GTPase activity of McrBC restriction complexes

  2020cited by this paper
• A nucleotide-sensing endonuclease from the Gabija bacterial defense system

  2020cited by this paper
• Diverse enzymatic activities mediate antiviral immunity in prokaryotes

  2020cited by this paper
• Epigenetic Regulation of Virulence and Immunoevasion by Phase-Variable Restriction-Modification Systems in Bacterial Pathogens.

  2020cited by this paper
• Antirestriction Protein ArdB (R64) Interacts with DNA

  2020cited by this paper
• Single-site DNA cleavage by Type III restriction endonuclease requires a site-bound enzyme and a trans-acting enzyme that are ATPase-activated

  2018cited by this paper
• DNA phosphorothioate modification—a new multi-functional epigenetic system in bacteria

  2018cited by this paper
• Avoidance of recognition sites of restriction-modification systems is a widespread but not universal anti-restriction strategy of prokaryotic viruses

  2018cited by this paper
• Systematic discovery of antiphage defense systems in the microbial pangenome

  2018cited by this paper
• Does Treatment Order Matter? Investigating the Ability of Bacteriophage to Augment Antibiotic Activity against Staphylococcus aureus Biofilms

  2018cited by this paper
• A Type I Restriction-Modification System Associated with Enterococcus faecium Subspecies Separation

  2018cited by this paper
• A model for the evolution of prokaryotic DNA restriction-modification systems based upon the structural malleability of Type I restriction-modification enzymes

  2018cited by this paper
• UbaLAI is a monomeric Type IIE restriction enzyme

  2017cited by this paper
• DISARM is a widespread bacterial defence system with broad anti-phage activities

  2017cited by this paper
• Distribution of Type I Restriction–Modification Systems in Streptococcus suis: An Outlook

  2016cited by this paper
• The Epigenomic Landscape of Prokaryotes

  2016cited by this paper
• Novel m4C modification in type I restriction-modification systems

  2016influential reference
• The Role of DNA Restriction-Modification Systems in the Biology of Bacillus anthracis

  2016cited by this paper
• The antibiotic resistance crisis: part 1: causes and threats.

  2015cited by this paper
• DNA-guided DNA interference by a prokaryotic Argonaute

  2014cited by this paper
• Restriction Enzyme Body Doubles and PCR Cloning: On the General Use of Type IIS Restriction Enzymes for Cloning

  2014cited by this paper
• REBASE—a database for DNA restriction and modification: enzymes, genes and genomes

  2014cited by this paper
• BREX is a novel phage resistance system widespread in microbial genomes

  2014cited by this paper
• Rebooting the genome: The role of negative feedback in horizontal gene transfer

  2014cited by this paper
• Type III restriction endonucleases are heterotrimeric: comprising one helicase–nuclease subunit and a dimeric methyltransferase that binds only one specific DNA

  2014cited by this paper
• Type I restriction enzymes and their relatives

  2013cited by this paper
• The Helicase-Like Domains of Type III Restriction Enzymes Trigger Long-Range Diffusion Along DNA

  2013cited by this paper
• Structural and Functional Analysis of the Symmetrical Type I Restriction Endonuclease R.EcoR124INT

  2012cited by this paper
• Phosphorothioate DNA as an antioxidant in bacteria

  2012cited by this paper
• Structure and operation of the DNA-translocating type I DNA restriction enzymes.

  2012cited by this paper
• Removal of a frameshift between the hsdM and hsdS genes of the EcoKI Type IA DNA restriction and modification system produces a new type of system and links the different families of Type I systems

  2012cited by this paper
• [Comparative analysis of antirestriction activity of R64 ArdA and ArdB proteins].

  2012cited by this paper
• Crystal structure and mechanism of action of the N6-methyladenine-dependent type IIM restriction endonuclease R.DpnI

  2012cited by this paper
• Deletion of One Nucleotide within the Homonucleotide Tract Present in the hsdS Gene Alters the DNA Sequence Specificity of Type I Restriction-Modification System NgoAV

  2011cited by this paper
• A type III-like restriction endonuclease functions as a major barrier to horizontal gene transfer in clinical Staphylococcus aureus strains

  2010cited by this paper
• A putative mobile genetic element carrying a novel type IIF restriction-modification system (PluTI)

  2010cited by this paper
• Structural and Functional Analysis of the Engineered Type I DNA Methyltransferase EcoR124INT

  2010cited by this paper
• The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain

  2009cited by this paper
• Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1

  2009cited by this paper
• REBASE—a database for DNA restriction and modification: enzymes, genes and genomes

  2009cited by this paper
• Structural and evolutionary classification of Type II restriction enzymes based on theoretical and experimental analyses

  2008cited by this paper
• Functional Analysis of MmeI from Methanol Utilizer Methylophilus methylotrophus, a Subtype IIC Restriction-Modification Enzyme Related to Type I Enzymes

  2008cited by this paper
• Comparative analysis of anti-restriction activities of ArdA (ColIb-P9) and Ocr (T7) proteins

  2008cited by this paper
• Plasmid-encoded antirestriction protein ArdA can discriminate between type I methyltransferase and complete restriction-modification system.

  2007cited by this paper
• A novel DNA modification by sulfur: DndA is a NifS-like cysteine desulfurase capable of assembling DndC as an iron-sulfur cluster protein in Streptomyces lividans.

  2007cited by this paper
• R.KpnI, an HNH superfamily REase, exhibits differential discrimination at non-canonical sequences in the presence of Ca2+ and Mg2+

  2007influential reference
• Phosphorothioation of DNA in bacteria by dnd genes.

  2007influential reference
• Tetrameric restriction enzymes: expansion to the GIY-YIG nuclease family

  2007cited by this paper
• Phosphorylation of Type IA restriction-modification complex enzyme EcoKI on the HsdR subunit.

  2007cited by this paper
• Generation of DNA cleavage specificities of type II restriction endonucleases by reassortment of target recognition domains

  2007cited by this paper
• Sau1: a Novel Lineage-Specific Type I Restriction-Modification System That Blocks Horizontal Gene Transfer into Staphylococcus aureus and between S. aureus Isolates of Different Lineages

  2006cited by this paper
• Structural model for the multisubunit Type IC restriction–modification DNA methyltransferase M.EcoR124I in complex with DNA

  2006cited by this paper
• High-resolution crystal structure of the restriction-modification controller protein C.AhdI from Aeromonas hydrophila.

  2005cited by this paper
• The biology of restriction and anti-restriction.

  2005influential reference
• Exogenous AdoMet and its analogue sinefungin differentially influence DNA cleavage by R.EcoP15I--usefulness in SAGE.

  2005cited by this paper
• Therapeutic use of phage cocktail for controlling Escherichia coli O157:H7 in gastrointestinal tract of mice.

  2005cited by this paper
• Crystal structure of DNA sequence specificity subunit of a type I restriction-modification enzyme and its functional implications.

  2005cited by this paper
• Restriction and modification in Bacillus subtilis: Identification of a gene in the temperate phage SPβ coding for a BsuR specific modification methyltransferase

  2004cited by this paper
• S-Adenosyl-L-methionine–Dependent Restriction Enzymes

  2004cited by this paper
• A restriction map of the bacteriophage T4 genome

  2004cited by this paper
• Ca2+-mediated Site-specific DNA Cleavage and Suppression of Promiscuous Activity of KpnI Restriction Endonuclease*

  2004cited by this paper
• Influence of phage T3 and T7 gene functions on a type III (EcoP1) DNA restriction-modification system in vivo

  2004cited by this paper
• New restriction enzymes discovered from Escherichia coli clinical strains using a plasmid transformation method.

  2003cited by this paper
• Maize Genome Sequencing by Methylation Filtration

  2003cited by this paper
• A nomenclature for restriction enzymes, DNA methyltransferases, homing endonucleases and their genes.

  2003cited by this paper
• Plasmid R16 ArdA Protein Preferentially Targets Restriction Activity of the Type I Restriction-Modification System EcoKI

  2003cited by this paper
• Diversity of type II restriction endonucleases that require two DNA recognition sites.

  2003cited by this paper
• Structure of Ocr from bacteriophage T7, a protein that mimics B-form DNA.

  2002cited by this paper
• Identification of genes that are associated with DNA repeats in prokaryotes

  2002cited by this paper
• Characterization of BseMII, a new type IV restriction-modification system, which recognizes the pentanucleotide sequence 5'-CTCAG(N)(10/8)/.

  2001influential reference
• Subunit assembly and mode of DNA cleavage of the type III restriction endonucleases EcoP1I and EcoP15I.

  2001cited by this paper
• S-adenosyl-L-methionine is required for DNA cleavage by type III restriction enzymes.

  2001cited by this paper
• Domain structure and subunit interactions in the type I DNA methyltransferase M.EcoR124I.

  2001cited by this paper
• Methyl-specific DNA binding by McrBC, a modification-dependent restriction enzyme.

  2000cited by this paper
• The McrBC endonuclease translocates DNA in a reaction dependent on GTP hydrolysis.

  1999cited by this paper
• Phage abortive infection of Bacillus licheniformis ATCC 9800; identification of the abiBL11 gene and localisation and sequencing of its promoter region

  1999cited by this paper
• A family of phase-variable restriction enzymes with differing specificities generated by high-frequency gene rearrangements.

  1998cited by this paper
• Structural, functional, and evolutionary relationships between lambda-exonuclease and the type II restriction endonucleases.

  1998cited by this paper
• The DNA recognition subunit of the type IB restriction-modification enzyme EcoAI tolerates circular permutions of its polypeptide chain.

  1998cited by this paper
• The role of metals in catalysis by the restriction endonuclease Bam HI

  1998cited by this paper

• CRISPR–Cas-Mediated Reprogramming Strategies to Overcome Antimicrobial Resistance

  2026cites this paper
• Considerations of Bacterial Robustness and Stability to Improve Bioprocess Design

  2026cites this paper
• A methylome-derived m6-dAMP trigger assembles a PUA-Cal-HAD immune filament that depletes dNTPs to abort phage infection

  2026cites this paper