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<p>Nucleic acid modifying enzymes drive diverse defense and counter-defense measures in the evolutionary arms race between viruses and their cellular hosts. Abundant and widespread bacterial viruses (bacteriophage or phage) encode for biosynthetic pathways that install elaborate DNA hypermodifications which protect their genomic DNA from host endonucleases. Here, we establish the molecular basis for the multistep biosynthesis of 6-aminocarboxymethyl-2ʹ-deoxyadenosine (6-<i>N</i>cmdA), a nucleobase hypermodification found in the virion DNA of bacteriophage Mu that leads to restriction evasion in the context of phage-host conflicts. In the first step, we show that Mu-encoded Mom enzyme catalyzes the formation of 6-<i>N</i>cmdA by transferring glycine from charged tRNA<sup>Gly</sup> to the N6 position of adenine within double-stranded DNA. We uncover a second step where the glycyl-dA intermediate undergoes an on-base rearrangement to form 6-<i>N</i>cmdA. Examination of the proposed reaction pathways by quantum chemical calculations confirms the instability of acyl exocyclic groups at N6-adenine and reveals an energetically favorable orientation of 6-<i>N</i>cmdA that restores canonical base pairing. An X-ray structure confirms Mom is a member of the GNAT superfamily and suggests binding sites for both tRNA and DNA. Guided by the Mom structure and patterns of sequence conservation across metagenomic space, we show residues R111 and S124 are essential for catalysis. This work demonstrates that the Mom enzyme defines a new category of acetyltransferases utilizing charged tRNA to modify DNA.</p>

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A single viral enzyme drives tRNA-dependent hypermodification of DNA at adenine

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月3日

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  • Rebekah M. B. Silva,
  • Anton Slyvka,
  • Yan-Jiun Lee,
  • Chudi Guan,
  • Sean R. Lund,
  • Elisabeth A. Raleigh,
  • Krzysztof Skowronek,
  • Michael S. Kuska,
  • Matthias Bochtler,
  • Peter R. Weigele

摘要

Nucleic acid modifying enzymes drive diverse defense and counter-defense measures in the evolutionary arms race between viruses and their cellular hosts. Abundant and widespread bacterial viruses (bacteriophage or phage) encode for biosynthetic pathways that install elaborate DNA hypermodifications which protect their genomic DNA from host endonucleases. Here, we establish the molecular basis for the multistep biosynthesis of 6-aminocarboxymethyl-2ʹ-deoxyadenosine (6-NcmdA), a nucleobase hypermodification found in the virion DNA of bacteriophage Mu that leads to restriction evasion in the context of phage-host conflicts. In the first step, we show that Mu-encoded Mom enzyme catalyzes the formation of 6-NcmdA by transferring glycine from charged tRNAGly to the N6 position of adenine within double-stranded DNA. We uncover a second step where the glycyl-dA intermediate undergoes an on-base rearrangement to form 6-NcmdA. Examination of the proposed reaction pathways by quantum chemical calculations confirms the instability of acyl exocyclic groups at N6-adenine and reveals an energetically favorable orientation of 6-NcmdA that restores canonical base pairing. An X-ray structure confirms Mom is a member of the GNAT superfamily and suggests binding sites for both tRNA and DNA. Guided by the Mom structure and patterns of sequence conservation across metagenomic space, we show residues R111 and S124 are essential for catalysis. This work demonstrates that the Mom enzyme defines a new category of acetyltransferases utilizing charged tRNA to modify DNA.