Pathways of thymidine hypermodification

Yan Jiun Lee, Nan Dai, Stephanie I. Müller, Chudi Guan, Mackenzie J. Parker, Morgan E. Fraser, Shannon E. Walsh, Janani Sridar, Andrew Mulholland, Krutika Nayak, Zhiyi Sun, Yu Cheng Lin, Donald G. Comb, Katherine Marks, Reyaz Gonzalez, Daniel P. Dowling, Vahe Bandarian, Lana Saleh, Ivan R. Corrêa, Peter R. Weigele*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


The DNAs of bacterial viruses are known to contain diverse, chemically complex modifications to thymidine that protect them from the endonuclease-based defenses of their cellular hosts, but whose biosynthetic origins are enigmatic. Up to half of thymidines in the Pseudomonas phage M6, the Salmonella phage ViI, and others, contain exotic chemical moieties synthesized through the post-replicative modification of 5-hydroxymethyluridine (5-hmdU). We have determined that these thymidine hypermodifications are derived from free amino acids enzymatically installed on 5-hmdU. These appended amino acids are further sculpted by various enzyme classes such as radical SAM isomerases, PLP-dependent decarboxylases, flavin-dependent lyases and acetyltransferases. The combinatorial permutations of thymidine hypermodification genes found in viral metagenomes from geographically widespread sources suggests an untapped reservoir of chemical diversity in DNA hypermodifications.

Original languageEnglish
Pages (from-to)3001-3017
Number of pages17
JournalNucleic acids research
Issue number6
StatePublished - 8 Apr 2022


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