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TitleTranslational regulation by oxidative desulfuration of tRNA modifications.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateMar 10, 2026
AuthorsYufeng Mo / Kensuke Ishiguro / Kenjyo Miyauchi / Yuriko Sakaguchi / Yosei Hanzawa / Naho Akiyama / Ayaka Murayama / Kodai Machida / Hiroaki Imataka / Akio Yamashita / Takayuki Ohira / Mikako Shirouzu / Tsutomu Suzuki /
PubMed AbstractModifications in the anticodon region of transfer RNA (tRNA) are essential for accurate and efficient protein synthesis. 5-Methyl-2-thiouridine derivatives (xmsU) are major modifications at the ...Modifications in the anticodon region of transfer RNA (tRNA) are essential for accurate and efficient protein synthesis. 5-Methyl-2-thiouridine derivatives (xmsU) are major modifications at the wobble position of tRNA anticodons decoding purine-ending two-codon sets. Although the thiocarbonyl group of xmsU enhances decoding efficiency, it is chemically susceptible to oxidative desulfuration, yielding 4-pyrimidinone derivatives (xmhU). Here, we identify xmhU derivatives in human cells and mouse tissues and confirm their cellular formation by spike-in experiments. Desulfurized tRNAs carrying 5-methoxycarbonylmethyl-4-pyrimidinone (mcmhU) show impaired codon recognition in a human reconstituted in vitro translation system. The mcmhU modification reduces aminoacylation of tRNAs for lysine, glutamate, and glutamine, but not arginine. Cryogenic electron microscopy reveals the structural basis of altered AAA/AAG decoding by mcmhU at the ribosomal A-site. These findings reveal a mechanism by which oxidative desulfuration of tRNA modifications dynamically regulates codon recognition and protein synthesis under oxidative stress conditions in human and mammalian cells.
External linksNat Commun / PubMed:41807381 / PubMed Central
MethodsEM (single particle)
Resolution2.26 - 3.18 Å
Structure data

EMDB-61706, PDB-9jpm:
Structure of the Bacterial Ribosome with human tRNA Lys(mcm5s2U34) and mRNA(AAA)
Method: EM (single particle) / Resolution: 2.43 Å

EMDB-61708, PDB-9jpo:
Structure of the Bacterial Ribosome with human tRNA Lys(mcm5h2U34) and mRNA(AAA)
Method: EM (single particle) / Resolution: 3.18 Å

EMDB-61709, PDB-9jpp:
Structure of the Bacterial Ribosome with human tRNA Lys(mcm5s2U34) and mRNA(AAG)
Method: EM (single particle) / Resolution: 2.26 Å

EMDB-61720, PDB-9jq2:
Structure of the Bacterial Ribosome with human tRNA Lys(mcm5h2U34) and mRNA(AAG)
Method: EM (single particle) / Resolution: 2.61 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

Source
  • escherichia coli (E. coli)
  • homo sapiens (human)
  • escherichia coli bw25113 (bacteria)
KeywordsRIBOSOME / tRNA modifications / decoding

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