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Transfer RNA modifications: nature's combinatorial chemistry playground

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Abstract Following synthesis, tRNAs are peppered by numerous chemical modifications which may differentially affect a tRNA's structure and function. Although modifications affecting the business ends of a tRNA are predictably important for cell viability, a majority of modifications play more subtle structural roles that can affect tRNA stability and folding. The current trend is that modifications act in concert and it is in the context of the specific sequence of a given tRNA that they impart their differing effects. Recent developments in the modification field have highlighted the diversity of modifications in tRNA. From these, the combinatorial nature of modifications in explaining previously described phenotypes derived from their absence has emerged as a growing theme. WIREs RNA 2013, 4:35–48. doi: 10.1002/wrna.1144 This article is categorized under: RNA Processing > RNA Editing and Modification RNA Processing > tRNA Processing

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Extreme chemical diversity among tRNA modification in biology. Modified nucleotides identified in at least one tRNA species are indicated in shaded spheres according to the domain(s) of life in which they are found. The modifications at the intersection of Eukarya and Bacteria enclosed by a box are modifications found in organelles, consistent with the proposed bacterial origins of these subcellular components. Commonly used symbols or abbreviations for the various modifications are as follows: mnX, methylation at position n of nucleotide base X; mn,nX, dimethylation at position n of nucleotide base X; snX, replacement of oxygen with sulfur at position n of nucleotide X; Xm, 2'‐O methylation of nucleotide X; D, dihydrouridine; Ψ, pseudouridine; ac4C, N‐4 acetylcytidine; i6A, N‐6 isopentenyladenosine; t6A, N‐6 threonyladenosine; g6A,N‐6 glycinylcarbamoyladenosine; io6A, N‐6 (cis‐hydroxyisopentenyl)adenosine; hn6A, N‐6 hydroxynorvalylcarbamoyladenosine; ac6A, N‐6 acetyladenosine; I, inosine (from deamination of adenosine); Xr(p), 2'‐O‐ribosyl phosphate derivative of nucleotide X; f5C, 5‐formyl cytosine; k2C, lysidine; agm2C, agmatidine; acp3U, 3‐(3‐amino‐3‐carboxypropyl)uridine; mcm5U, C‐5 methoxycarbonylmethyl uridine; nmn5U, C‐5 carbamoylmethyl uridine; chm5U, C‐5 carboxyhydroxymethyl uridine; ho5U, C‐5 hydroxyuridine; mo5U, C‐5 methoxyuridine; cmo5U, uridine 5‐oxyacetic acid; mcmo5U, uridine 5‐oxyacetic acid methyl ester; mnm5U, C‐5 methylaminomethyluridine; cmnm5U, C‐5 carboxymethylaminomethyluridine; nm5U, C‐5 aminomethyluridine; Q, queosine (and related 7‐deaza species oQ, preQ1, preQ0, gluQ, galQ, and manQ); G+, archaeosine; yW, wybutosine (and related OHyW, OHyW*, o2yW, and yW‐86 species), imG, wyosine (and related imG‐14, mimG, and imG2 species). Various combinations of the modifications listed above are indicated with combinations of multiple symbols; i.e., nmn5s2U = 5‐methylaminomethyl 2‐thio uridine. (Reprinted with permission from Ref 2. Copyright 2009 Landes Bioscience)

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Modified nucleotides in the context of two‐dimensional and three‐dimensional structures of tRNA. (a) The secondary structure of a typical type I tRNA is shown, with each ball indicating a single nucleotide. Positions that are known to be modified in Saccharomyces cerevisiae cytoplasmic tRNAs are highlighted in red. Although the exact positions that are modified vary between tRNAs from different species and different domains of life, the general pattern of modification, with a high density of modifications observed in the anticodon stem–loop and many fewer modified nucleotides observed in the aminoacyl‐acceptor stem, is retained in most species. (b) The three‐dimensional structure of yeast tRNAPhe (PDB ID 4TNA), with modified nucleotides that are observed in this tRNAPhe species, is highlighted in red on the structure. These include modifications that are found universally in a large number of tRNAs throughout all three domains of life (such as the m5U5455 that gives the so‐called TΨ stem its name) as well as modifications such as the wybutosine base (yW37) that are more specific to tRNAPhe from Eukarya and Archaea.

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Additional chemical complexity of tRNA modifications is observed in selected organisms. (a) The wybutosine (yW) modification found at position 37 of eukaryotic tRNAPhe is the result of a multistep biosynthetic process; the proposed biosynthetic pathway in yeast is indicated by the various shaded groups, each of which represents a distinct step of yW production. In higher eukaryotes and many Archaea, the yW modification is further elaborated into several derivatives, including the OHyW that is the product of TYW5 action in humans. (b) The carboxymethyluridine modification and its derivatives found at position 34 of several tRNAs in eukaryotes. Functional groups added to yield the indicated nucleotide species in parentheses are shown in colored circles. All of these species are related by the common presence of the cm5U modification, synthesized by a common set of enzymes.

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Modified nucleotides found in tRNA in all three domains of life. Chemical groups added as modifications to purine and pyrimidine rings to create the 18 ‘universal’ tRNA modifications are shown, with arrows indicating the atom of the ring that is modified and common abbreviated name for each modified nucleotide indicated in parentheses. The C1‐N6 and C4‐N3 bonds of the purine and pyrimidine rings, respectively, are highlighted in red to indicate that the bonding order depends on the identity of the nucleotide base, with single bonds in the case of G and U, and double bonds in the case of A and C.

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RNA Processing > tRNA Processing

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