Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), Howard Hughes Medical Institute (HHMI), European Research Council (ERC)
Primary Citation of Related Structures: 9H6Y, 9H74
PubMed Abstract:
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.
Organizational Affiliation:
Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China.
INSERM U1212 Acides Nucléiques-Régulations Naturelle et Artificielle (ARNA), Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France.
INSERM U1212 Acides Nucléiques-Régulations Naturelle et Artificielle (ARNA), Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France. yaser.hashem@uni-hamburg.de.
Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA. sq38@cornell.edu.
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