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Naturally occurring modified ribonucleosides

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Abstract The chemical identity of RNA molecules beyond the four standard ribonucleosides has fascinated scientists since pseudouridine was characterized as the “fifth” ribonucleotide in 1951. Since then, the ever‐increasing number and complexity of modified ribonucleosides have been found in viruses and throughout all three domains of life. Such modifications can be as simple as methylations, hydroxylations, or thiolations, complex as ring closures, glycosylations, acylations, or aminoacylations, or unusual as the incorporation of selenium. While initially found in transfer and ribosomal RNAs, modifications also exist in messenger RNAs and noncoding RNAs. Modifications have profound cellular outcomes at various levels, such as altering RNA structure or being essential for cell survival or organism viability. The aberrant presence or absence of RNA modifications can lead to human disease, ranging from cancer to various metabolic and developmental illnesses such as Hoyeraal–Hreidarsson syndrome, Bowen–Conradi syndrome, or Williams–Beuren syndrome. In this review article, we summarize the characterization of all 143 currently known modified ribonucleosides by describing their taxonomic distributions, the enzymes that generate the modifications, and any implications in cellular processes, RNA structure, and disease. We also highlight areas of active research, such as specific RNAs that contain a particular type of modification as well as methodologies used to identify novel RNA modifications. This article is categorized under: RNA Processing > RNA Editing and Modification
Ribonucleoside numbering of adenine, guanine, cytosine, uracil bases and numbering of the ribose sugar for adenosine (A), guanosine (G), cytidine (C), and uridine (U). Carbon atoms are in gray, oxygen atoms are in red, and nitrogen atoms are in blue. Single lines between atoms depict single bonds, double lines between atoms depict double bonds, and hydrogens are not depicted for simplicity
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Scheme for cmnm5U, cm5U, τm5U, s2U, se2U, and related derivatives. Shown in red are chemical modifications that occur in the production of 5‐methyluridine or thiolated uridine derivatives: m5U or rT, cmnm5U, mnm5U, nm5U, cm5U, mcm5U, chm5U, mchm5U, nchm5U, ncm5U, τm5U, s2U, m5s2U or s2T, cmnm5s2U, mnm5s2U, nm5s2U, τm5s2U, mcm5s2U, ncm5s2U, cm5s2U, se2U, ges2U, cmnm5ges2U, mnm5ges2U, cmnm5se2U, and mnm5se2U. Modifications containing a 2‐thio group, a 2‐geranyl group, or a 2‐seleno group are listed with only abbreviations, while the structures for s2U, ges2U, and se2U are shown as exemplars for each of these modification types. Enzymes that catalyze each reaction are adjacent to arrow, otherwise a question mark (?) indicates enzyme is unknown. Arrow tails containing red, blue, or yellow ellipses denote reactions that occur in archaea, bacteria, or eukaryotes, respectively
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Scheme for wybutosine derivatives. Chemical modifications (red) that occur in the production of wybutosine derived from guanosine (G) include: m1G, imG‐14, imG, imG2, mimG, yW‐86, yW‐72, yW‐58, yW, OHyW*, OHyWy, o2yW, and OHyW. Enzymes that catalyze each reaction are adjacent to arrow, otherwise a question mark (?) indicates enzyme is unknown. Arrow tails containing red, blue, or yellow ellipses denote reactions that occur in archaea, bacteria, or eukaryotes, respectively. The bolded numbers 1 and 3 are added to indicate position N1 and N3, respectively, in guanosine
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Scheme for queuosine derivatives. Pathway depicts the modifications that occur during the production of queuosine derivatives preQ0, preQ1, oQ, Q, GalQ, ManQ, GluQ, and G+. Red color indicates the modification added to the guanosine molecule. Enzymes that catalyze each reaction are adjacent to arrow. The plus sign by GluQ indicates that glutamate is incorporated onto one of the hydroxyl groups from Q, though it is unknown at present which of the two hydroxyl groups receives the glutamate. Arrow tails containing red, blue, or yellow ellipses denote reactions that occur in archaea, bacteria, or eukaryotes, respectively
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Chemical structures of all currently known RNA modifications. Adenosine‐derived (yellow), guanosine‐derived (pink), uridine‐derived (purple), and cytidine‐derived (cyan) modifications are classified based on the parent ribonucleoside. Red moieties indicate which portion of the modified ribonucleoside is different from the parent ribonucleoside, whose structures are shown in the central circle. A poster‐size image is available as Figure S1
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Schemes showing the production of i6A and t6A derivatives of adenosine. (a) Modifications that occur in the production of i6A, io6A, ms2i6A, ms2io6A, and msms2i6A. (b) Modifications that occur in the production of g6A, t6A, ht6A, ms2t6A, m6t6A, ct6A, and ms2ct6A. In both panels, arrows denote enzymatic reactions and enzyme(s) that participate in each reaction are abbreviated if known (see abbreviations list) or denoted by a question mark (?) if unknown. Red moieties represent the modification(s) added to the adenosine molecule. Arrow tails containing red, blue, or yellow ellipses denote reactions that occur in archaea, bacteria, or eukaryotes, respectively
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tRNA‐specific modifications are clustered around specific nucleotides in tRNAs. A schematic of the secondary structure of tRNA is depicted as a cloverleaf structure, having a D‐loop (purple), an anticodon loop (orange), a TΨC‐loop (blue), and the 3′‐CCA sequence (green) that is aminoacylated when charged with an amino acid (AA). Numbers refer to specific nucleotide positions where modifications have been mapped (Lorenz, Lünse, & Mörl, ; Phillips & de Crécy‐Lagard, ; Phizicky & Hopper, ; Powell, Nicholls, & Minczuk, ). The modifications cataloged in Table occur at numbered positions in Figure
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Euler diagrams showing the currently known phylogenetic distribution of ribonucleoside modifications in tRNA, rRNA, mRNA, and ncRNA classes. Archaeal modifications are in pink, bacterial modifications are in blue, and eukaryotic modifications are in yellow
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