Hypermodified DNA in Viruses of E. coli and Salmonella

The DNA in bacterial viruses collectively contains a rich, yet relatively underexplored, chemical diversity of nucleobases beyond the canonical adenine, guanine, cytosine, and thymine. Herein, we review what is known about the genetic and biochemical basis for the biosynthesis of complex DNA modifications, also called DNA hypermodifications, in the DNA of tailed bacteriophages infecting Escherichia coli and Salmonella enterica. These modifications, and their diversification, likely arose out of the evolutionary arms race between bacteriophages and their cellular hosts. Despite their apparent diversity in chemical structure, the syntheses of various hypermodified bases share some common themes. Hypermodifications form through virus-directed synthesis of noncanonical deoxyribonucleotide triphosphates, direct modification DNA, or a combination of both. Hypermodification enzymes are often encoded in modular operons reminiscent of biosynthetic gene clusters observed in natural product biosynthesis. The study of phage-hypermodified DNA provides an exciting opportunity to expand what is known about the enzyme-catalyzed chemistry of nucleic acids and will yield new tools for the manipulation and interrogation of DNA.