Bacteria are engaged in a perpetual molecular arms race with bacteriophages, the viruses that infect them. Phages inject genetic material into bacterial cells and redirect cellular machinery toward producing new viral particles. To survive, bacteria have evolved an expanding arsenal of defence systems, including enzymes that recognize, destroy or chemically alter invading DNA. A study published in Nature Microbiology now identifies DNA glycosylases as a widespread and previously underappreciated class of bacterial antiviral proteins, revealing that enzymes traditionally linked to genome maintenance can also function as targeted weapons against phage infection.
The research, led by L. J. Getz, A. L. Qian, Vivian Liu and colleagues, focused on a central challenge in phage biology: how bacteria detect viral DNA when that DNA has been chemically modified to evade immune surveillance. Many phages alter their genomes by replacing standard nucleobases or adding chemical groups to them. These modifications can protect viral DNA from restriction enzymes and other bacterial defences, but they also create unusual molecular patterns. The new findings show that bacteria can exploit those patterns through specialized DNA glycosylases that selectively recognize modified bases in phage genomes.
DNA glycosylases are best known as components of DNA repair pathways. In conventional repair, a glycosylase scans DNA and identifies a damaged or chemically altered base, then cleaves the bond connecting that base to the sugar-phosphate backbone. This generates an abasic site, which can subsequently be processed by additional repair enzymes. By removing the abnormal base rather than cutting the DNA backbone directly, glycosylases provide a precise mechanism for correcting chemical damage while limiting unnecessary disruption to the chromosome.
The study shows that some members of this enzyme class have been repurposed for antiviral defence. Using structure-guided discovery, the researchers identified two widespread families of anti-phage glycosylases, named Dag1 and Dag2. Although these proteins are related to the broader DNA glycosylase fold, their biological role is distinct from routine repair. Dag1 and Dag2 act as immune effectors that preferentially target phage DNA containing modified guanine bases, allowing bacteria to distinguish invading genomes from their own unmodified genetic material.
This selectivity is important because a defence enzyme that indiscriminately damaged every chemically unusual base could also threaten the host chromosome. Phage genomes, however, may carry modifications that are rare or absent in bacterial DNA. By recognizing these non-canonical forms of guanine, Dag1 and Dag2 can focus their activity on viral DNA during infection. The resulting base removal is expected to produce lesions that compromise the integrity or replication of the phage genome, thereby reducing the virus’s ability to generate progeny.
Rather than relying solely on sequence comparisons, the researchers used the conserved three-dimensional architecture of glycosylases as a guide for finding additional defence proteins. This approach allowed them to search for structurally related enzymes that may have diverged so extensively at the sequence level that conventional genome-mining methods would overlook them. The resulting collection included numerous defence-associated glycosylases, suggesting that the antiviral use of this fold is not limited to Dag1 and Dag2 but represents a broad and diverse evolutionary strategy.
The diversity of these enzymes also points to a wider chemical contest between bacteria and phages. Phages are known to deploy an array of modified bases, including altered guanine and thymidine derivatives, to make their DNA resistant to bacterial nucleases and other immune mechanisms. In response, bacteria appear to have evolved glycosylases with different molecular specificities. The newly described systems collectively form a repertoire capable of targeting chemically modified phage DNA, potentially matching the variety of base modifications found across viral lineages.
The researchers further identified a distinct glycosylase superfamily associated with protection against phages carrying modified thymidine bases. Its separation from the Dag1 and Dag2 families indicates that bacteria have recruited more than one structural solution to the same broad problem: detecting and neutralizing viral genomes that contain non-standard nucleobases. The discovery expands the known functional range of glycosylases and illustrates how common biochemical frameworks can be adapted to recognize chemically distinct targets.
These findings have implications beyond the specific defence systems described in the study. Bacterial genomes contain many proteins whose functions remain unknown, particularly among rapidly evolving defence islands enriched in genes involved in phage resistance. Structure-guided analysis may reveal immune functions that are invisible to sequence-based annotation, helping researchers map the hidden architecture of bacterial antiviral biology. The work also underscores the evolutionary flexibility of DNA repair enzymes, which can be redeployed from preserving genetic information to attacking an invading genome.
As phage therapy, synthetic biology and microbiome research continue to develop, understanding these mechanisms could become increasingly important. Bacterial glycosylases may influence which phages can infect particular hosts, while phage base modifications may determine whether an infection succeeds or fails. The study establishes DNA glycosylases as a versatile class of bacterial immune proteins and demonstrates that the molecular signatures created by phage genome modification can become liabilities. In the continuing conflict between bacteria and viruses, chemical camouflage may therefore provide protection—but it can also reveal the invader to a precisely adapted cellular defence.
Subject of Research: Antiviral DNA glycosylases that recognize and damage chemically modified phage DNA.
Article Title: Antiviral defence is a conserved function of diverse bacterial DNA glycosylases
Article References: Getz, L.J., Qian, A.L., Vivian Liu, Y. et al. Antiviral defence is a conserved function of diverse bacterial DNA glycosylases. Nature Microbiology (2026). https://doi.org/10.1038/s41564-026-02441-0
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41564-026-02441-0
Keywords: Bacteriophages, bacterial immunity, DNA glycosylases, modified DNA bases, phage defence, Dag1, Dag2, antiviral defence, genome modification, microbial evolution
