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<p>Bacteriophages possess a wide array of DNA modifications, with many acting as molecular camouflage to evade host immune defenses. Sequence databases contain numerous bacteriophage enzymes of unknown function, with some potentially involved in yet to be identified DNA modifications. Here we report the discovery of a DNA cytosine C5-carboxymethyltransferase (CmoX) in <i>Synechococcus</i> phage S-B43, which catalyzes the formation of a 5-carboxymethylcytosine (5cxmC), previously reported as an unnatural DNA modification formed by an engineered cytosine methyltransferase. The carboxy-S-adenosyl-L-methionine (Cx-SAM) cofactor required by CmoX is provided by a phage-encoded Cx-SAM synthase (CmoA), a homolog of the bacterial CmoA involved in tRNA modification. A crystal structure of CmoX in complex with Cx-SAM revealed the basis for its substrate selectivity, involving a key Arg residue interacting with the substrate carboxy group. In addition, we characterize a phage-encoded ATP-dependent amide ligase, CmoY that catalyzes the formation of 5cxmC-glycine amide. CmoA is present in many bacteriophage genomes, typically alongside CmoX and homologs of CmoY, suggesting that 5cxmC modification is a widespread naturally occurring DNA modification serving as a handle for further hypermodifications in bacteriophages. Our study underscores the ability of bacteriophages to repurpose RNA modification enzymes to expand their repertoire of DNA modifications.</p>

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Carboxymethylcytosine is a natural base modification and a handle for bacteriophage DNA hypermodification

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月7日

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  • Qiaoyu Yang,
  • Lin Zhang,
  • Yantao Liang,
  • Haoyu Ma,
  • Lifu Song,
  • Lin Luo,
  • Jason Tan,
  • Yiling Hu,
  • Kailiang Ma,
  • Yiwei Chen,
  • Yang Tong,
  • Chuyuan Zhang,
  • Suwen Zhao,
  • Min Wang,
  • Liang Zhang,
  • Yifeng Wei,
  • Yan Zhang

摘要

Bacteriophages possess a wide array of DNA modifications, with many acting as molecular camouflage to evade host immune defenses. Sequence databases contain numerous bacteriophage enzymes of unknown function, with some potentially involved in yet to be identified DNA modifications. Here we report the discovery of a DNA cytosine C5-carboxymethyltransferase (CmoX) in Synechococcus phage S-B43, which catalyzes the formation of a 5-carboxymethylcytosine (5cxmC), previously reported as an unnatural DNA modification formed by an engineered cytosine methyltransferase. The carboxy-S-adenosyl-L-methionine (Cx-SAM) cofactor required by CmoX is provided by a phage-encoded Cx-SAM synthase (CmoA), a homolog of the bacterial CmoA involved in tRNA modification. A crystal structure of CmoX in complex with Cx-SAM revealed the basis for its substrate selectivity, involving a key Arg residue interacting with the substrate carboxy group. In addition, we characterize a phage-encoded ATP-dependent amide ligase, CmoY that catalyzes the formation of 5cxmC-glycine amide. CmoA is present in many bacteriophage genomes, typically alongside CmoX and homologs of CmoY, suggesting that 5cxmC modification is a widespread naturally occurring DNA modification serving as a handle for further hypermodifications in bacteriophages. Our study underscores the ability of bacteriophages to repurpose RNA modification enzymes to expand their repertoire of DNA modifications.