Journal
NUCLEIC ACIDS RESEARCH
Volume 49, Issue 9, Pages 4877-4890Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab289
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Funding
- Irish Cancer Society [ICS/CRSIIFER]
- King Abdullah Scholarship
- Enterprise Ireland [CF/2011/1603, CF/2015/0020P]
- Science Foundation Ireland [SFI] [IvP 13/IA/1894]
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Base modification can occur throughout a transfer RNA molecule, with a particular emphasis on position 34 of the anticodon loop. Human enzymes can recognize a wide range of artificial derivatives for transfer RNA incorporation, while displaying strict specificity for decoding certain codons. Exploiting the queuosine incorporation pathway shows broad potential for intentionally engineering chemical diversity into transfer RNA anticodons.
Base-modification can occur throughout a transfer RNA molecule; however, elaboration is particularly prevalent at position 34 of the anticodon loop (the wobble position), where it functions to influence protein translation. Previously, we demonstrated that the queuosine modification at position 34 can be substituted with an artificial analogue via the queuine tRNA ribosyltransferase enzyme to induce disease recovery in an animal model of multiple sclerosis. Here, we demonstrate that the human enzyme can recognize a very broad range of artificial 7-deazaguanine derivatives for transfer RNA incorporation. By contrast, the enzyme displays strict specificity for transfer RNA species decoding the dual synonymous NAU/C codons, determined using a novel enzyme-RNA capture-release method. Our data highlight the broad scope and therapeutic potential of exploiting the queuosine incorporation pathway to intentionally engineer chemical diversity into the transfer RNA anticodon.
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