Epitranscriptome: Review of Top 25 Most-Studied RNA Modifications
Abstract
:1. Introduction
2. Current Status of Research on RNA Modifications
3. RNA Modifications at Large
4. RNA Modifications in Depth
4.1. N6-methyladenosine (m6A)
4.2. Inosine (I) and 1-methylinosine (m1I)
4.3. Pseudouridine (Ψ)
4.4. 5-methyluridine (m5U)
4.5. 2′-O-methylation of ribose (Nm or 2’-O-Me)
4.6. 1-methyladenosine (m1A)
4.7. Dihydrouridine
4.8. N4-acetylcytidine (ac4C)
4.9. Methyluridine (m3U)
4.10. 5-methylcytidine (m5C) and 5-formylcytidine (f5C)
4.11. 7-methylguanosine (m7G)
4.12. tRNA Structural Modifications
5. Conclusions and Perspectives
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Modification | Code | Base | Domains | RNA Classes | Location and Frequency | Function | Methods | Diseases | Ref. |
---|---|---|---|---|---|---|---|---|---|
N6-methyladenosine | m6A | A | All | rRNA, tRNA, mRNA, miRNA, lncRNA, circRNA, snRNA | mRNA: enriched in 5′-UTRs, around stop codons, and in 3′ UTRs | mRNA: regulates splicing events, induces mRNA instability, increases translation efficiency; lncRNA: plays a role in lncRNA-mediated transcriptional repression | DRS, HPLC MeRIP-seq, MiCLIP | Osteoporosis, HCC, obesity | [21,22,23,24,25,26,27] |
Inosine | I | A | All | tRNA, mRNA, miRNA | tRNA: p. 34, 37, 57; mRNA: dsRNA regions | tRNA: required for wobble codon recognition; mRNA: affects stability and localization, can change protein sequence | LC-MS/MS, RT-PCR, DRS, de novo RNA-seq | HCC; gastric, colorectal, esophageal, glioblastoma, and lung cancers | [28,29,30,31,32,33] |
Pseudouridine | Ψ or Y | U | All | rRNA, tRNA, mRNA, snRNA, Mt-tRNA, scaRNA, snoRNA, miRNA, lincRNA | tRNA: p. 55; mRNA: 5′UTR, 3′UTR, CDS | rRNA: plays a role in ribosome assembly and translational fidelity; tRNA: increases stability | Pseudo-Seq, DRS, PSI-seq, CeU-Seq, Ψ-Seq, RBS-seq | Prostate, breast, and lung cancers; HCC | [34,35,36,37,38,39,40,41] |
7-methylguanosine | m7G | G | All | miRNA, rRNA, mRNA, tRNA, | rRNA: SSU G1639 (in humans); tRNA: p. 46; mRNA: 4522 clusters within 2318 mRNAs in 293T cells | tRNA: increases stability; mRNA: regulates translation | m7G-MeRIP-seq, m7G-seq, DRS, m7G-miCLIP-seq, m7G-MaP-seq | HCC, PAD, lung cancer | [35,42,43,44,45,46,47,48] |
Dihydrouridine | D | U | All | tRNA, mRNA, snoRNA | tRNA: p. 16, 17, 20, 20a, 20b, 47; mRNA: 130 sites in 112 transcripts in S. cerevisiae; snoRNA: 48 sites in 23 snoRNA in S. cerevisiae | tRNA: destabilizes the structure; mRNA: affects splicing and translation | D-seq, Rho-seq, LC-MS | Lung cancer | [49,50,51,52,53] |
N1-methyladenosine | m1A | A | All | rRNA, tRNA, mRNA, lncRNA | rRNA: p.1322 in 28S; tRNA: p. 9, 14, 16, 22, 57, 58; mRNA: rare | rRNA: ensures proper folding; tRNA: ensures stability and proper folding | ARM-seq, m1A-seq, m1A-quant-seq, m1A-ID-seq, m1A-seq-SS, m1A-seq-TGIR, m1A-MAP, m1A-IP-seq | HCC; cervical, pancreatic, breast, and ovarian cancers | [17,54,55,56,57,58,59] |
Queuosine | Q | G | Bacteria,eukaryotes | tRNA | tRNATyr, tRNAHis, tRNAAsn, tRNAAsp: p. 34 (humans) | Impacts coding potential of tRNA, protects tRNA from ribonuclease cleavage | UHPLC-MS/MS, LC-MC | T-cell lymphoma, colon cancer | [60,61,62,63] |
5-methylcytidine | m5C | C | All | rRNA, tRNA, mRNA, eRNA, miRNA, lncRNA, viral RNA, vault RNA, snRNA, snoRNA | rRNA: m5C3761 and m5C4413 (well-conserved in eukaryotes); tRNA: variable loop, anticodon loop, and T stem; mRNA: enriched in 5′UTR | rRNA: ensures proper folding and translational fidelity; tRNA: ensures proper folding and stability, codon–anticodon interactions, and reading frame maintenance; mRNA: affects stability, translation rate; lncRNA: affects stability; vault RNA: required for biogenesis | m5C-RIP-seq, Aza-IP-seq, miCLIP-seq, TAWO-seq, RNA-BisSeq, RBS-seq, DRS, MeRIP-seq | ARID, DS, lactic acidosis, breast cancer, hypotonia /floppy baby syndrome, metabolism | [14,40,48,64,65,66,67] |
5-formylcytidine | f5C | C | All | tRNA | mt-tRNAMet: p.C34 (always) | Required for decoding of AUA codon in mitochondria | HPLC-MS | NA | [68,69] |
5-methyluridine | m5U | U | All | rRNA, tRNA | tRNA: p. 54 | Ensures fidelity of translation, folding, and stability of tRNA | FICC-Seq, iCLIP, miCLIP-seq | Breast cancer, systemic lupus erythematosus | [70,71,72,73] |
2′-O-methylation | Nm | All | All | rRNA, tRNA, mRNA, snRNA, snoRNA | mRNA: 5′UTR, 3′UTR, CDS; tRNA: p. 4 | Nm increases the thermodynamic stability of RNA:RNA base pairs and stabilizes A-form RNA duplexes | RiboMethSeq, 2D-TLC, Nm-seq, 2′OMe-seq, RTL-P, DRS, RibOxi-seq | Asthma, Alzheimer’s disease | [48,74,75,76,77,78,79] |
1-methylguanosine | m1G | G | All | tRNA, mRNA | tRNALeuCUN, tRNAProCCN, tRNAArgCGG: p. 37 (always); tRNA: p. 9 (always in S. cerevisiae); mRNA (0.00046% G in S. cerevisiae) | tRNA: prevents frameshifting; mRNA: reduces translation fidelity in a position- and codon-dependent manner | MR-FISH, LC-MS/MS, DRS | NA | [80,81,82,83,84,85,86] |
5-methylaminomethyl- 2-thiouridine | mnm5s2U | U | All | tRNA | tRNALys3UUU: p. 34 (always) | Required for decoding of the lysine codons AAA and AAG by tRNALys3UUU | LC-MS/MS | NA | [87,88,89] |
Wybutosine | yW | G | Archaea, eukaryotes | tRNA | tRNAPhe: p. 37 (often) | Stabilizes codon–anticodon interactions | LC-MS/MS | NA | [90,91] |
N4-acetylcytidine | ac4C | C | All | rRNA, tRNA, mRNA | tRNA: p. 12 (always); rRNA: in helix 34, 45; mRNA: enriched in 5′UTR and CDS (4250 sites in HeLa; not present in HEK293; 0.1% C in S. cerevisiae mRNA) | tRNA: increases translation efficiency and accuracy; mRNA: increases stability | acRIP-seq, ac4C-seq | NA | [92,93,94,95] |
3-methylcytidine | m3C | C | Eukaryotes | tRNA | tRNA: p. 32 (30–90%, depending on tRNA) | Unknown | AlkAniline-seq, HAC-seq, ARM-seq, DM-tRNA-seq, mim-tRNA-seq, hydro-tRNA-seq, LC-MS/MS, NAIL-MS | Several types of cancer | [57,96,97,98,99,100,101] |
Archaeosine | G+ | G | Archaea | tRNA | tRNA: p. 15 (always), p.13 (in some species) | Increases thermal stability of tRNA | HPLC | NA | [102,103] |
5-methoxycarbonylmethyl- 2-thiouridine | mcm5s2U | U | Eukaryotes | tRNA | tRNALysUUU, tRNAGluUUC, tRNAGlnUUG: p. 34 (always) | Improves decoding efficiency of tRNA | HPLC-MS | NA | [88,104] |
2-thiocytidine | s2C | C | Bacteria, eukaryotes | tRNA | tRNAArg, tRNASer2GCU: p. 32 (always) | Restricts recognition of certain wobble codons | HPLC-MS | NA | [105,106] |
N2,N2-dimethylguanosine | m2,2G | G | Archaea, eukaryotes | tRNA, mRNA | tRNA: p. 10, p. 26 (always); mRNA (0.00051% G in S. cerevisiae) | tRNA: plays a role in tRNA folding and prevents tRNA from adopting wrong conformation; mRNA: reduces translation fidelity in a position- and codon-dependent manner | PhOxi-seq, LC-MS/MS | NA | [82,107,108] |
N6-isopentenyladenosine | i6A | A | Bacteria, eukaryotes | tRNA | tRNAUNN: p. A37 (always) | Increases translation fidelity and efficiency of cognate codons | PHA6 assay, HPLC, Sanger | NA | [109,110,111] |
N6-threonylcarbamoyladenosine | t6A | A | All | tRNA | tRNAANN: p. A37 (always) | Facilitates codon–anticodon pairing and prevents frameshift during protein synthesis | LC-MS/MS | MERFF, neurodegeneration, diabetes | [110,111,112] |
3-methyluridine | m3U | U | All | rRNA, tRNA | rRNA: U1498 (always in E. coli 16S), U2634 U2843 (in S. cerevisiae 25S); tRNAThr: p.U32 (always in T. brucei) | Unknown | MR-FISH, RP-HPLC | NA | [85,113,114] |
Wyosine | imG | G | Archaea | tRNA | tRNAPhe: p. 37 (often) | Stabilizes codon–anticodon interactions | HPLC-MS | NA | [115,116] |
1-methylinosine | m1I | I | Bacteria, archaea, eukaryotes | tRNA | tRNAAla: p. 37 (eukaryotes); tRNA: p. 57 (archaea) | Unknown | LC-MS/MS | NA | [83,117] |
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Arzumanian, V.A.; Dolgalev, G.V.; Kurbatov, I.Y.; Kiseleva, O.I.; Poverennaya, E.V. Epitranscriptome: Review of Top 25 Most-Studied RNA Modifications. Int. J. Mol. Sci. 2022, 23, 13851. https://doi.org/10.3390/ijms232213851
Arzumanian VA, Dolgalev GV, Kurbatov IY, Kiseleva OI, Poverennaya EV. Epitranscriptome: Review of Top 25 Most-Studied RNA Modifications. International Journal of Molecular Sciences. 2022; 23(22):13851. https://doi.org/10.3390/ijms232213851
Chicago/Turabian StyleArzumanian, Viktoriia A., Georgii V. Dolgalev, Ilya Y. Kurbatov, Olga I. Kiseleva, and Ekaterina V. Poverennaya. 2022. "Epitranscriptome: Review of Top 25 Most-Studied RNA Modifications" International Journal of Molecular Sciences 23, no. 22: 13851. https://doi.org/10.3390/ijms232213851
APA StyleArzumanian, V. A., Dolgalev, G. V., Kurbatov, I. Y., Kiseleva, O. I., & Poverennaya, E. V. (2022). Epitranscriptome: Review of Top 25 Most-Studied RNA Modifications. International Journal of Molecular Sciences, 23(22), 13851. https://doi.org/10.3390/ijms232213851