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词条 RNA modification
释义

  1. Technologies

      Next generation sequencing    Mass Spectrometry  

  2. Function

      Messenger RNA modification    Transfer RNA modifications    Ribosomal RNA modification  

  3. Types

  4. DataBases

  5. References

RNA modification occurs in all living organisms, and is one of the most evolutionarily conserved properties of Ribonucleic acid or RNAs.[1][2][3] It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.[1][2][3][4]

More than 160 types of RNA modifications have been described so far,[5] recent studies have revealed they are abundant in tRNAs and in regulatory non-coding RNAs (e.g., lncRNAs, miRNAs, snRNAs, snoRNAs) as well as in mRNAs and rRNAs.[4]

Technologies

Next generation sequencing

To identify diverse post-transcriptional modifications of RNA molecules and determine the transcriptome-wide landscape of RNA modifications by means of next generation RNA sequencing, recently many studies have developed conventional[6] or specialised sequencing methods.[1][2][3] Examples of specialised methods are MeRIP-seq,[7] m6A-seq,[8] methylation-iCLIP,[9] m6A-CLIP,[10] Pseudo-seq,[11] Ψ-seq,[12] CeU-seq,[13] Aza-IP[14] and RiboMeth-seq[15]). Application of these methods have identified various modifications (e.g. pseudouridine, m6A, m5C, 2′-O-Me) within coding genes and non-coding genes (e.g. tRNA, lncRNAs, microRNAs) at single nucleotide or very high resolution.[4] A novel database, RMBase (http://mirlab.sysu.edu.cn/rmbase/),[4] has provide various web interfaces to show all RNA modification sites identified from above-mentioned sequencing technologies.

Mass Spectrometry

Mass spectrometry is a way to qualitatively and (relatively) quantify RNA modifications.[16] More often than not, modifications cause an increase in mass for a given nucleoside. This gives a characteristic readout for the nucleoside and the modified counterpart.[16]

Function

Messenger RNA modification

Recently, functional experiments have revealed many novel functional roles of RNA modifications. For example, m6A has been predicted to affect protein translation and localization,[1][2][3] mRNA stability,[17] alternative polyA choice [10] and stem cell pluripotency.[18] Pseudouridylation of nonsense codons suppresses translation termination both in vitro and in vivo, suggesting that RNA modification may provide a new way to expand the genetic code.[19] Importantly, many modification enzymes are dysregulated and genetically mutated in many disease types.[1] For example, genetic mutations in pseudouridine synthases cause mitochondrial myopathy, sideroblastic anemia (MLASA) [20] and dyskeratosis congenital.[21]

Transfer RNA modifications

Transfer RNA or tRNA is the most abundantly modified type of RNA.[22] Modifications in tRNA play crucial roles in maintaining translation efficiency through supporting structure, anticodon-codon interactions, and interactions with enzymes.[23]

Anticodon modifications are important for proper decoding of mRNA. Since the genetic code is degenerate, anticodon modifications are necessary to properly decode mRNA. Particularly, the wobble position of the anticodon determines how the codons are read. For example, in eukaryotes an adenosine at position 34 of the anticodon can be converted to inosine. Inosine is a modification that is able to base-pair with cytosine, adenine, and uridine.[24]

Another commonly modified base in tRNA is the position adjacent to the anticodon. Position 37 is often hypermodified with bulky chemical modifications. These modifications prevent frameshifting and increase anticodon-codon binding stability through stacking interactions[25].

Ribosomal RNA modification

Ribosomal RNA modifications are made throughout the ribosome synthesis. Modifications primarily play a role in the structure of the rRNA in order to protect translational efficiency[26].

Types

There are over 160 RNA modifications identified[42]. Chemical modifications can range from simple methylations (m6A) to hypermodifications (i6A) that require several steps for synthesis[42]. Hypermodified bases are primarily seen at position 34 and 37 of the tRNA anticodon. Other examples of hypermodifications include (but not limited to) 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine (ms2io6A), 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U), and 7-aminocarboxypropyl-demethylwyosine (yW)[42].

The location of the modification on the nucleoside may also vary. It is possible for the sugar group (ribose) to be modified and/or the base of the nucleoside[42].

DataBases

Name Description type Link References
RMBaseRMBase is designed for decoding the landscape of RNA modifications identified from high-throughput sequencing data (Pseudo-seq, Ψ-seq, CeU-seq, Aza-IP, MeRIP-seq, m6A-seq, m6A-CLIP, RiboMeth-seq). It demonstrated thousands of RNA modifications located within mRNAs, regulatory ncRNAs (e.g. lncRNAs, miRNAs), miRNA target sites and disease-related SNPs. database website [27][28]
MODOMICSMODOMICS is a database of RNA modifications that provides comprehensive information concerning the chemical structures of modified ribonucleosides, their biosynthetic pathways, RNA-modifying enzymes and location of modified residues in RNA sequences. database website [29][30]
RNAMDBRNAMDB has served as a focal point for information pertaining to naturally occurring RNA modifications database website [31]
3D Ribosomal Modification MapsA reference database that has sequences of mapped ribosomal RNAs with visualization tools in 2D and 3D.databasewebsite[32]
.

References

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2. ^1 2 3 {{cite journal | vauthors = Song CX, Yi C, He C | title = Mapping recently identified nucleotide variants in the genome and transcriptome | journal = Nature Biotechnology | volume = 30 | issue = 11 | pages = 1107–16 | date = November 2012 | pmid = 23138310 | pmc = 3537840 | doi = 10.1038/nbt.2398 }}
3. ^1 2 3 {{cite journal | vauthors = Meyer KD, Jaffrey SR | title = The dynamic epitranscriptome: N6-methyladenosine and gene expression control | journal = Nature Reviews. Molecular Cell Biology | volume = 15 | issue = 5 | pages = 313–26 | date = May 2014 | pmid = 24713629 | pmc = 4393108 | doi = 10.1038/nrm3785 }}
4. ^1 2 3 {{cite journal | vauthors = Sun WJ, Li JH, Liu S, Wu J, Zhou H, Qu LH, Yang JH | title = RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data | journal = Nucleic Acids Research | volume = 44 | issue = D1 | pages = D259-65 | date = January 2016 | pmid = 26464443 | pmc = 4702777 | doi = 10.1093/nar/gkv1036 }}
5. ^{{cite journal | vauthors = Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, de Crécy-Lagard V, Ross R, Limbach PA, Kotter A, Helm M, Bujnicki JM | title = MODOMICS: a database of RNA modification pathways. 2017 update | journal = Nucleic Acids Research | volume = 46 | issue = D1 | pages = D303–D307 | date = January 2018 | pmid = 29106616 | pmc = 5753262 | doi = 10.1093/nar/gkx1030 }}
6. ^"Accurate Mapping of tRNA Reads"; Anne Hoffmann et al.; Bioinformatics, btx756, https://doi.org/10.1093/bioinformatics/btx756
7. ^{{cite journal | vauthors = Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR | title = Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons | journal = Cell | volume = 149 | issue = 7 | pages = 1635–46 | date = June 2012 | pmid = 22608085 | pmc = 3383396 | doi = 10.1016/j.cell.2012.05.003 }}
8. ^{{cite journal | vauthors = Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G | title = Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq | journal = Nature | volume = 485 | issue = 7397 | pages = 201–6 | date = April 2012 | pmid = 22575960 | doi = 10.1038/nature11112 }}
9. ^{{cite journal | vauthors = Hussain S, Sajini AA, Blanco S, Dietmann S, Lombard P, Sugimoto Y, Paramor M, Gleeson JG, Odom DT, Ule J, Frye M | title = NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs | journal = Cell Reports | volume = 4 | issue = 2 | pages = 255–61 | date = July 2013 | pmid = 23871666 | pmc = 3730056 | doi = 10.1016/j.celrep.2013.06.029 }}
10. ^1 {{cite journal | vauthors = Ke S, Alemu EA, Mertens C, Gantman EC, Fak JJ, Mele A, Haripal B, Zucker-Scharff I, Moore MJ, Park CY, Vågbø CB, Kusśnierczyk A, Klungland A, Darnell JE, Darnell RB | title = A majority of m6A residues are in the last exons, allowing the potential for 3' UTR regulation | journal = Genes & Development | volume = 29 | issue = 19 | pages = 2037–53 | date = October 2015 | pmid = 26404942 | pmc = 4604345 | doi = 10.1101/gad.269415.115 }}
11. ^{{cite journal | vauthors = Carlile TM, Rojas-Duran MF, Zinshteyn B, Shin H, Bartoli KM, Gilbert WV | title = Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells | journal = Nature | volume = 515 | issue = 7525 | pages = 143–6 | date = November 2014 | pmid = 25192136 | pmc = 4224642 | doi = 10.1038/nature13802 }}
12. ^{{cite journal | vauthors = Schwartz S, Bernstein DA, Mumbach MR, Jovanovic M, Herbst RH, León-Ricardo BX, Engreitz JM, Guttman M, Satija R, Lander ES, Fink G, Regev A | title = Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA | journal = Cell | volume = 159 | issue = 1 | pages = 148–162 | date = September 2014 | pmid = 25219674 | pmc = 4180118 | doi = 10.1016/j.cell.2014.08.028 }}
13. ^{{cite journal | vauthors = Li X, Zhu P, Ma S, Song J, Bai J, Sun F, Yi C | title = Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome | journal = Nature Chemical Biology | volume = 11 | issue = 8 | pages = 592–7 | date = August 2015 | pmid = 26075521 | doi = 10.1038/nchembio.1836 }}
14. ^{{cite journal | vauthors = Khoddami V, Cairns BR | title = Identification of direct targets and modified bases of RNA cytosine methyltransferases | journal = Nature Biotechnology | volume = 31 | issue = 5 | pages = 458–64 | date = May 2013 | pmid = 23604283 | pmc = 3791587 | doi = 10.1038/nbt.2566 }}
15. ^{{cite journal | vauthors = Birkedal U, Christensen-Dalsgaard M, Krogh N, Sabarinathan R, Gorodkin J, Nielsen H | title = Profiling of ribose methylations in RNA by high-throughput sequencing | journal = Angewandte Chemie | volume = 54 | issue = 2 | pages = 451–5 | date = January 2015 | pmid = 25417815 | doi = 10.1002/anie.201408362 }}
16. ^1 {{cite journal | vauthors = Wetzel C, Limbach PA | title = Mass spectrometry of modified RNAs: recent developments | journal = The Analyst | volume = 141 | issue = 1 | pages = 16–23 | date = January 2016 | pmid = 26501195 | pmc = 4679475 | doi = 10.1039/C5AN01797A }}
17. ^{{cite journal | vauthors = Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C | title = N6-methyladenosine-dependent regulation of messenger RNA stability | journal = Nature | volume = 505 | issue = 7481 | pages = 117–20 | date = January 2014 | pmid = 24284625 | pmc = 3877715 | doi = 10.1038/nature12730 }}
18. ^{{cite journal | vauthors = Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben-Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G, Hanna JH | title = Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation | journal = Science | volume = 347 | issue = 6225 | pages = 1002–6 | date = February 2015 | pmid = 25569111 | doi = 10.1126/science.1261417 }}
19. ^{{cite journal | vauthors = Karijolich J, Yu YT | title = Converting nonsense codons into sense codons by targeted pseudouridylation | journal = Nature | volume = 474 | issue = 7351 | pages = 395–8 | date = June 2011 | pmid = 21677757 | pmc = 3381908 | doi = 10.1038/nature10165 }}
20. ^{{cite journal | vauthors = Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N | title = Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA) | journal = American Journal of Human Genetics | volume = 74 | issue = 6 | pages = 1303–8 | date = June 2004 | pmid = 15108122 | pmc = 1182096 | doi = 10.1086/421530 }}
21. ^{{cite journal | vauthors = Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, Poustka A, Dokal I | title = X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions | journal = Nature Genetics | volume = 19 | issue = 1 | pages = 32–8 | date = May 1998 | pmid = 9590285 | doi = 10.1038/ng0598-32 }}
22. ^{{cite journal | vauthors = Kirchner S, Ignatova Z | title = Emerging roles of tRNA in adaptive translation, signalling dynamics and disease | journal = Nature Reviews. Genetics | volume = 16 | issue = 2 | pages = 98–112 | date = February 2015 | pmid = 25534324 | doi = 10.1038/nrg3861 }}
23. ^{{cite journal | vauthors = Lorenz C, Lünse CE, Mörl M | title = tRNA Modifications: Impact on Structure and Thermal Adaptation | journal = Biomolecules | volume = 7 | issue = 2 | pages = 35 | date = April 2017 | pmid = 28375166 | pmc = 5485724 | doi = 10.3390/biom7020035 }}
24. ^{{cite journal | vauthors = Agris PF, Vendeix FA, Graham WD | title = tRNA's wobble decoding of the genome: 40 years of modification | journal = Journal of Molecular Biology | volume = 366 | issue = 1 | pages = 1–13 | date = February 2007 | pmid = 17187822 | doi = 10.1016/j.jmb.2006.11.046 | url = https://www.sciencedirect.com/science/article/pii/S0022283606015865 }}
25. ^{{cite journal | vauthors = Agris PF, Vendeix FA, Graham WD | title = tRNA's wobble decoding of the genome: 40 years of modification | journal = Journal of Molecular Biology | volume = 366 | issue = 1 | pages = 1–13 | date = February 2007 | pmid = 17187822 | doi = 10.1016/j.jmb.2006.11.046 | url = https://www.sciencedirect.com/science/article/pii/S0022283606015865 }}
26. ^{{Cite journal|last=Sloan|first=Katherine|display-authors=etal|date=2016|title=Tuning the ribosome: The influence of rRNA modification on eukaryotic ribosome biogenesis and function.|url=|journal=RNA Biology|volume=14|issue=9|pages=1138–1152|via=|doi=10.1080/15476286.2016.1259781|pmid=27911188|pmc=5699541}}
27. ^{{cite journal | vauthors = Xuan JJ, Sun WJ, Lin PH, Zhou KR, Liu S, Zheng LL, Qu LH, Yang JH | title = RMBase v2.0: deciphering the map of RNA modifications from epitranscriptome sequencing data | journal = Nucleic Acids Research | volume = 46 | issue = D1 | pages = D327–D334 | date = January 2018 | pmid = 29040692 | pmc = 5753293 | doi = 10.1093/nar/gkx934 }}
28. ^{{cite journal | vauthors = Sun WJ, Li JH, Liu S, Wu J, Zhou H, Qu LH, Yang JH | title = RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data | journal = Nucleic Acids Research | volume = 44 | issue = D1 | pages = D259-65 | date = January 2016 | pmid = 26464443 | doi = 10.1093/nar/gkv1036 }}
29. ^1 2 3 4 {{cite journal | vauthors = Machnicka MA, Milanowska K, Osman Oglou O, Purta E, Kurkowska M, Olchowik A, Januszewski W, Kalinowski S, Dunin-Horkawicz S, Rother KM, Helm M, Bujnicki JM, Grosjean H | title = MODOMICS: a database of RNA modification pathways--2013 update | journal = Nucleic Acids Research | volume = 41 | issue = Database issue | pages = D262-7 | date = January 2013 | pmid = 23118484 | pmc = 3531130 | doi = 10.1093/nar/gks1007 }}
30. ^{{cite journal | vauthors = Limbach PA, Crain PF, McCloskey JA | title = Summary: the modified nucleosides of RNA | journal = Nucleic Acids Research | volume = 22 | issue = 12 | pages = 2183–96 | date = June 1994 | pmid = 7518580 | pmc = 523672 | doi = 10.1093/nar/22.12.2183 }}
31. ^{{cite journal | vauthors = Cantara WA, Crain PF, Rozenski J, McCloskey JA, Harris KA, Zhang X, Vendeix FA, Fabris D, Agris PF | title = The RNA Modification Database, RNAMDB: 2011 update | journal = Nucleic Acids Research | volume = 39 | issue = Database issue | pages = D195-201 | date = January 2011 | pmid = 21071406 | pmc = 3013656 | doi = 10.1093/nar/gkq1028 }}
32. ^{{cite journal | vauthors = Piekna-Przybylska D, Decatur WA, Fournier MJ | title = The 3D rRNA modification maps database: with interactive tools for ribosome analysis | journal = Nucleic Acids Research | volume = 36 | issue = Database issue | pages = D178-83 | date = January 2008 | pmid = 17947322 | pmc = 2238946 | doi = 10.1093/nar/gkm855 | url = https://academic.oup.com/nar/article/36/suppl_1/D178/2507247 }}

3 : RNA splicing|RNA|Gene expression
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