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TitleProgrammable initiation of mRNA translation by trans-RNA.
Journal, issue, pagesNat Biotechnol, Year 2025
Publish dateNov 21, 2025
AuthorsLongfei Jia / Tan-Trung Nguyen / Saori Uematsu / Yifei Gu / Shengcho Shi / Yaser Hashem / Shu-Bing Qian /
PubMed AbstractSeveral approaches exist to silence genes, but few tools are available to activate individual mRNAs for translation inside cells. Guiding ribosomes to specific start codons without altering the ...Several approaches exist to silence genes, but few tools are available to activate individual mRNAs for translation inside cells. Guiding ribosomes to specific start codons without altering the original sequence remains a formidable task. Here we design capped trans-RNAs capable of directing ribosomes to specific initiation sites on individual mRNAs when the trans-cap is positioned near the target start codon. Structural and biochemical data suggest that the capped trans-RNA facilitates ribosome loading and scanning on the target mRNA through a synergistic mechanism involving alternative cap recognition. The trans-RNA also acts independently of the cap on the target mRNA, enabling translation of circular RNAs lacking internal ribosome entry sites. We apply trans-RNAs in vivo to achieve programmable alternative translation of endogenous genes in mouse liver. Finally, we provide the evidence for the existence of natural transcripts that, similarly to exogenous trans-RNAs, activate translation of endogenous mRNAs.
External linksNat Biotechnol / PubMed:41272315
MethodsEM (single particle)
Resolution2.9 Å
Structure data

51903

9h6y

EMDB-51903, PDB-9h6y:
Late-stage 48S Initiation Complex (LS48S IC) guided by the trans-RNA
Method: EM (single particle) / Resolution: 2.9 Å

51911

9h74

EMDB-51911, PDB-9h74:
Late-stage 48S Initiation Complex with eIF3 (LS48S-eIF3 IC) guided by the trans-RNA
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-SF4:
IRON/SULFUR CLUSTER

Source
  • oryctolagus cuniculus (rabbit)
KeywordsTRANSLATION / 48S late-stage initiation complex / Programmable mRNA translation initiation / trans-RNA / activation of mRNA translation

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