Biology:RNA modification

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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

Adenosine is one of the four canonical bases in RNA. Above are some examples of chemical modifications that have biological functions. Information was gathered from Modomics Database of RNA Modifications

There are over 160 RNA modifications identified[27]. Chemical modifications can range from simple methylations (m6A) to hypermodifications (i6A) that require several steps for synthesis[27]. 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)[27].

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[27].

DataBases

Name Description type Link References
RMBase RMBase 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 [28][29]
MODOMICS MODOMICS 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 [27][30]
RNAMDB RNAMDB has served as a focal point for information pertaining to naturally occurring RNA modifications database website [31]
3D Ribosomal Modification Maps A reference database that has sequences of mapped ribosomal RNAs with visualization tools in 2D and 3D. database website [32]
.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "The pivotal regulatory landscape of RNA modifications". Annual Review of Genomics and Human Genetics 15: 127–50. 2013. doi:10.1146/annurev-genom-090413-025405. PMID 24898039. 
  2. ↑ 2.0 2.1 2.2 2.3 "Mapping recently identified nucleotide variants in the genome and transcriptome". Nature Biotechnology 30 (11): 1107–16. November 2012. doi:10.1038/nbt.2398. PMID 23138310. 
  3. ↑ 3.0 3.1 3.2 3.3 "The dynamic epitranscriptome: N6-methyladenosine and gene expression control". Nature Reviews. Molecular Cell Biology 15 (5): 313–26. May 2014. doi:10.1038/nrm3785. PMID 24713629. 
  4. ↑ 4.0 4.1 4.2 4.3 "RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data". Nucleic Acids Research 44 (D1): D259-65. January 2016. doi:10.1093/nar/gkv1036. PMID 26464443. 
  5. ↑ "MODOMICS: a database of RNA modification pathways. 2017 update". Nucleic Acids Research 46 (D1): D303–D307. January 2018. doi:10.1093/nar/gkx1030. PMID 29106616. 
  6. ↑ "Accurate Mapping of tRNA Reads"; Anne Hoffmann et al.; Bioinformatics, btx756, https://doi.org/10.1093/bioinformatics/btx756
  7. ↑ "Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons". Cell 149 (7): 1635–46. June 2012. doi:10.1016/j.cell.2012.05.003. PMID 22608085. 
  8. ↑ "Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq". Nature 485 (7397): 201–6. April 2012. doi:10.1038/nature11112. PMID 22575960. 
  9. ↑ "NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs". Cell Reports 4 (2): 255–61. July 2013. doi:10.1016/j.celrep.2013.06.029. PMID 23871666. 
  10. ↑ 10.0 10.1 "A majority of m6A residues are in the last exons, allowing the potential for 3' UTR regulation". Genes & Development 29 (19): 2037–53. October 2015. doi:10.1101/gad.269415.115. PMID 26404942. 
  11. ↑ "Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells". Nature 515 (7525): 143–6. November 2014. doi:10.1038/nature13802. PMID 25192136. 
  12. ↑ "Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA". Cell 159 (1): 148–162. September 2014. doi:10.1016/j.cell.2014.08.028. PMID 25219674. 
  13. ↑ "Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome". Nature Chemical Biology 11 (8): 592–7. August 2015. doi:10.1038/nchembio.1836. PMID 26075521. 
  14. ↑ "Identification of direct targets and modified bases of RNA cytosine methyltransferases". Nature Biotechnology 31 (5): 458–64. May 2013. doi:10.1038/nbt.2566. PMID 23604283. 
  15. ↑ "Profiling of ribose methylations in RNA by high-throughput sequencing". Angewandte Chemie 54 (2): 451–5. January 2015. doi:10.1002/anie.201408362. PMID 25417815. 
  16. ↑ 16.0 16.1 "Mass spectrometry of modified RNAs: recent developments". The Analyst 141 (1): 16–23. January 2016. doi:10.1039/C5AN01797A. PMID 26501195. 
  17. ↑ "N6-methyladenosine-dependent regulation of messenger RNA stability". Nature 505 (7481): 117–20. January 2014. doi:10.1038/nature12730. PMID 24284625. 
  18. ↑ "Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation". Science 347 (6225): 1002–6. February 2015. doi:10.1126/science.1261417. PMID 25569111. 
  19. ↑ "Converting nonsense codons into sense codons by targeted pseudouridylation". Nature 474 (7351): 395–8. June 2011. doi:10.1038/nature10165. PMID 21677757. 
  20. ↑ "Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)". American Journal of Human Genetics 74 (6): 1303–8. June 2004. doi:10.1086/421530. PMID 15108122. 
  21. ↑ "X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions". Nature Genetics 19 (1): 32–8. May 1998. doi:10.1038/ng0598-32. PMID 9590285. 
  22. ↑ "Emerging roles of tRNA in adaptive translation, signalling dynamics and disease". Nature Reviews. Genetics 16 (2): 98–112. February 2015. doi:10.1038/nrg3861. PMID 25534324. 
  23. ↑ "tRNA Modifications: Impact on Structure and Thermal Adaptation". Biomolecules 7 (2): 35. April 2017. doi:10.3390/biom7020035. PMID 28375166. 
  24. ↑ "tRNA's wobble decoding of the genome: 40 years of modification". Journal of Molecular Biology 366 (1): 1–13. February 2007. doi:10.1016/j.jmb.2006.11.046. PMID 17187822. 
  25. ↑ "tRNA's wobble decoding of the genome: 40 years of modification". Journal of Molecular Biology 366 (1): 1–13. February 2007. doi:10.1016/j.jmb.2006.11.046. PMID 17187822. 
  26. ↑ Sloan, Katherine (2016). "Tuning the ribosome: The influence of rRNA modification on eukaryotic ribosome biogenesis and function.". RNA Biology 14 (9): 1138–1152. doi:10.1080/15476286.2016.1259781. PMID 27911188. 
  27. ↑ 27.0 27.1 27.2 27.3 27.4 "MODOMICS: a database of RNA modification pathways--2013 update". Nucleic Acids Research 41 (Database issue): D262-7. January 2013. doi:10.1093/nar/gks1007. PMID 23118484. 
  28. ↑ "RMBase v2.0: deciphering the map of RNA modifications from epitranscriptome sequencing data". Nucleic Acids Research 46 (D1): D327–D334. January 2018. doi:10.1093/nar/gkx934. PMID 29040692. 
  29. ↑ "RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data". Nucleic Acids Research 44 (D1): D259-65. January 2016. doi:10.1093/nar/gkv1036. PMID 26464443. 
  30. ↑ "Summary: the modified nucleosides of RNA". Nucleic Acids Research 22 (12): 2183–96. June 1994. doi:10.1093/nar/22.12.2183. PMID 7518580. 
  31. ↑ "The RNA Modification Database, RNAMDB: 2011 update". Nucleic Acids Research 39 (Database issue): D195-201. January 2011. doi:10.1093/nar/gkq1028. PMID 21071406. 
  32. ↑ "The 3D rRNA modification maps database: with interactive tools for ribosome analysis". Nucleic Acids Research 36 (Database issue): D178-83. January 2008. doi:10.1093/nar/gkm855. PMID 17947322. 




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