RNAs play several prominent roles in the cellular environment ranging from structural, messengers, translators, and effector molecules. RNA molecules while performing these roles are associated with several chemical modifications occurring post-transcriptionally, responsible for these supporting vital functions. The recent documentation of surface RNA modification with sialic acid residues has sparked advancement to the framework of RNA modifications. Glycan modification of surface RNA which was previously known to modify only proteins and lipids has opened new vistas to explore how these surface RNA modifications affect the cellular responses and phenotype. This paradigm shift in RNA biology with a vision of “glycans being all over the cells” has posed the field with a repertoire of questions and has given headway to the RNA world hypothesis. The review provides a comprehensive overview of glycoRNA discovery with a conceptual understanding of its previous underlying discoveries and their biological consequences with possible insights into the dynamic influence of this modification on their molecular versatility deciding cancer-immunology fate with potential implications of these glycosylation in cellular interaction, signaling, immune regulation, cancer evasion and proliferation.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Murn J, Shi Y. The winding path of protein methylation research: milestones and new frontiers. Nat Rev Mol Cell Biol. 2017;18:517–27.
Narita T, Weinert BT, Choudhary C. Author Correction: Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol. 2019;20:508.
Cohen P. The origins of protein phosphorylation. Nat Cell Biol. 2002;4:E127–30.
Swatek KN, Komander D. Ubiquitin modifications. Cell Res. 2016;26:399–422.
Spicer CD, Davis BG. Selective chemical protein modification. Nat Commun. 2014;5:4740.
Schubeler D. Function and information content of DNA methylation. Nature. 2015;517:321–6.
Wyatt GR. Occurrence of 5-methylcytosine in nucleic acids. Nature. 1950;166:237–8.
Adams JM, Cory S. Modified nucleosides and bizarre 5’-termini in mouse myeloma mRNA. Nature. 1975;255:28–33.
Perry RP, Kelley DE, Friderici K, Rottman F. The methylated constituents of L cell messenger RNA: evidence for an unusual cluster at the 5’ terminus. Cell. 1975;4:387–94.
Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169:1187–1200.
Norbury CJ. Cytoplasmic RNA: a case of the tail wagging the dog. Nat Rev Mol Cell Biol. 2013;14:643–53.
Chang H, Lim J, Ha M, Kim VN. TAIL-seq: genome-wide determination of poly(A) tail length and 3’ end modifications. Mol Cell. 2014;53:1044–52.
Sierant M, Leszczynska G, Sadowska K, Komar P, Radzikowska-Cieciura E, Sochacka E, et al. Escherichia coli tRNA 2-selenouridine synthase (SelU) converts S2U-RNA to Se2U-RNA via S-geranylated-intermediate. FEBS Lett. 2018;592:2248–58.
Kasai H, Nakanishi K, Macfarlane RD, Torgerson DF, Ohashi Z, McCloskey JA, et al. Letter: The structure of Q* nucleoside isolated from rabbit liver transfer ribonucleic acid. J Am Chem Soc. 1976;98:5044–6.
Sinha KM, Gu J, Chen Y, Reddy R. Adenylation of small RNAs in human cells. Development of a cell-free system for accurate adenylation on the 3’-end of human signal recognition particle RNA. J Biol Chem. 1998;273:6853–9.
Mullen TE, Marzluff WF. Degradation of histone mRNA requires oligouridylation followed by decapping and simultaneous degradation of the mRNA both 5’ to 3’ and 3’ to 5’. Genes Dev. 2008;22:50–65.
Rissland OS, Norbury CJ. Decapping is preceded by 3’ uridylation in a novel pathway of bulk mRNA turnover. Nat Struct Mol Biol. 2009;16:616–23.
Yoluc Y, Ammann G, Barraud P, Jora M, Limbach PA, Motorin Y, et al. Instrumental analysis of RNA modifications. Crit Rev Biochem Mol Biol. 2021;56:178–204.
Luo X, Li H, Liang J, Zhao Q, Xie Y, Ren J, et al. RMVar: an updated database of functional variants involved in RNA modifications. Nucleic Acids Res. 2021;49:D1405–D1412.
Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 2018;46:D303–D307.
Rottman F, Shatkin AJ, Perry RP. Sequences containing methylated nucleotides at the 5’ termini of messenger RNAs: possible implications for processing. Cell. 1974;3:197–9.
Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015;518:560–4.
Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell. 2015;162:1299–308.
Kawai G, Yamamoto Y, Kamimura T, Masegi T, Sekine M, Hata T, et al. Conformational rigidity of specific pyrimidine residues in tRNA arises from posttranscriptional modifications that enhance steric interaction between the base and the 2’-hydroxyl group. Biochemistry. 1992;31:1040–6.
Sheng J, Zhang W, Hassan AE, Gan J, Soares AS, Geng S, et al. Hydrogen bond formation between the naturally modified nucleobase and phosphate backbone. Nucleic Acids Res. 2012;40:8111–8.
Taoka M, Nobe Y, Yamaki Y, Sato K, Ishikawa H, Izumikawa K, et al. Landscape of the complete RNA chemical modifications in the human 80S ribosome. Nucleic Acids Res. 2018;46:9289–98.
Kim YK, Heo I, Kim VN. Modifications of small RNAs and their associated proteins. Cell. 2010;143:703–9.
Karijolich J, Yu YT. Spliceosomal snRNA modifications and their function. RNA Biol. 2010;7:192–204.
Trixl L, Lusser A. The dynamic RNA modification 5-methylcytosine and its emerging role as an epitranscriptomic mark. Wiley Interdiscip Rev RNA. 2019;10:e1510.
Keffer-Wilkes LC, Soon EF, Kothe U. The methyltransferase TrmA facilitates tRNA folding through interaction with its RNA-binding domain. Nucleic Acids Res. 2020;48:7981–90.
Di Timoteo G, Dattilo D, Centron-Broco A, Colantoni A, Guarnacci M, Rossi F, et al. Modulation of circRNA Metabolism by m(6)A Modification. Cell Rep. 2020;31:107641.
Yang Y, Fan X, Mao M, Song X, Wu P, Zhang Y, et al. Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res. 2017;27:626–41.
Chen YG, Chen R, Ahmad S, Verma R, Kasturi SP, Amaya L, et al. N6-methyladenosine modification controls circular RNA immunity. Mol Cell. 2019;76:96–109 e9.
Okada N, Nishimura S. Enzymatic synthesis of Q nucleoside containing mannose in the anticodon of tRNA: isolation of a novel mannosyltransferase from a cell-free extract of rat liver. Nucleic Acids Res. 1977;4:2931–8.
Flynn RA, Pedram K, Malaker SA, Batista PJ, Smith BAH, Johnson AG, et al. Small RNAs are modified with N-glycans and displayed on the surface of living cells. Cell. 2021;184:3109–24 e22.
Tarentino AL, Plummer TH Jr. Enzymatic deglycosylation of asparagine-linked glycans: purification, properties, and specificity of oligosaccharide-cleaving enzymes from Flavobacterium meningosepticum. Methods Enzymol. 1994;230:44–57.
Duan S, Paulson JC. Siglecs as immune cell checkpoints in disease. Annu Rev Immunol. 2020;38:365–95.
Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol. 2014;14:653–66.
Chang YC, Nizet V. Siglecs at the host-pathogen interface. Adv Exp Med Biol. 2020;1204:197–214.
Fraschilla I, Pillai S. Viewing Siglecs through the lens of tumor immunology. Immunol Rev. 2017;276:178–91.
Stanczak MA, Siddiqui SS, Trefny MP, Thommen DS, Boligan KF, von Gunten S, et al. Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells. J Clin Investig. 2018;128:4912–23.
Flores R, Zhang P, Wu W, Wang X, Ye P, Zheng P, et al. Siglec genes confer resistance to systemic lupus erythematosus in humans and mice. Cell Mol Immunol. 2019;16:154–64.
Angata T. Associations of genetic polymorphisms of Siglecs with human diseases. Glycobiology. 2014;24:785–93.
Wang Y, Neumann H. Alleviation of neurotoxicity by microglial human Siglec-11. J Neurosci. 2010;30:3482–8.
Tsai CM, Riestra AM, Ali SR, Fong JJ, Liu JZ, Hughes G, et al. Siglec-14 enhances NLRP3-inflammasome activation in macrophages. J innate Immun. 2020;12:333–43.
Liu YC, Yu MM, Chai YF, Shou ST. Sialic acids in the immune response during sepsis. Front Immunol. 2017;8:1601.
Huang N, Fan X, Zaleta-Rivera K, Nguyen TC, Zhou J, Luo Y, et al. Natural display of nuclear-encoded RNA on the cell surface and its impact on cell interaction. Genome Biol. 2020;21:225.
Janas T, Yarus M. Visualization of membrane RNAs. RNA. 2003;9:1353–61.
Morozkin ES, Laktionov PP, Rykova EY, Vlassov VV. Extracellular nucleic acids in cultures of long-term cultivated eukaryotic cells. Ann N. Y Acad Sci. 2004;1022:244–9.
Block KF, Puerta-Fernandez E, Wallace JG, Breaker RR. Association of OLE RNA with bacterial membranes via an RNA-protein interaction. Mol Microbiol. 2011;79:21–34.
Janas T, Janas T, Yarus M. Human tRNA(Sec) associates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers. RNA. 2012;18:2260–8.
Lin A, Hu Q, Li C, Xing Z, Ma G, Wang C, et al. The LINK-A lncRNA interacts with PtdIns(3,4,5)P3 to hyperactivate AKT and confer resistance to AKT inhibitors. Nat Cell Biol. 2017;19:238–51.
Hirschberg CB, Snider MD. Topography of glycosylation in the rough endoplasmic reticulum and Golgi apparatus. Annu Rev Biochem. 1987;56:63–87.
Aebi M. N-linked protein glycosylation in the ER. Bioch et Biophys Acta. 2013;1833:2430–7.
Hirschberg CB, Robbins PW, Abeijon C. Transporters of nucleotide sugars, ATP, and nucleotide sulfate in the endoplasmic reticulum and Golgi apparatus. Annu Rev Biochem. 1998;67:49–69.
Gandini R, Reichenbach T, Tan TC, Divne C. Structural basis for dolichylphosphate mannose biosynthesis. Nat Commun. 2017;8:120.
Moremen KW, Tiemeyer M, Nairn AV. Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol. 2012;13:448–62.
Helm M. Post-transcriptional nucleotide modification and alternative folding of RNA. Nucleic Acids Res. 2006;34:721–33.
Kruger K, Grabowski PJ, Zaug AJ, Sands J, Gottschling DE, Cech TR. Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena. Cell. 1982;31:147–57.
Guerrier-Takada C, Gardiner K, Marsh T, Pace N, Altman S. The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme. Cell. 1983;35:849–57.
Chan CT, Pang YL, Deng W, Babu IR, Dyavaiah M, Begley TJ, et al. Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins. Nat Commun. 2012;3:937.
Begley U, Dyavaiah M, Patil A, Rooney JP, DiRenzo D, Young CM, et al. Trm9-catalyzed tRNA modifications link translation to the DNA damage response. Mol Cell. 2007;28:860–70.
Endres L, Dedon PC, Begley TJ. Codon-biased translation can be regulated by wobble-base tRNA modification systems during cellular stress responses. RNA Biol. 2015;12:603–14.
Nachtergaele S, Krishnan Y. New Vistas for Cell-Surface GlycoRNAs. N. Engl J Med. 2021;385:658–60.
Silsirivanit A. Glycosylation markers in cancer. Adv Clin Chem. 2019;89:189–213.
Narayanan S. Sialic acid as a tumor marker. Ann Clin Lab Sci. 1994;24:376–84.
Boligan KF, Mesa C, Fernandez LE, von Gunten S. Cancer intelligence acquired (CIA): tumor glycosylation and sialylation codes dismantling antitumor defense. Cell Mol Life Sci. 2015;72:1231–48.
Pinho SS, Reis CA. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer. 2015;15:540–55.
Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164:1226–32.
Robertson JD. Membrane structure. J Cell Biol. 1981;91:189s–204s.
Singer SJ, Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science. 1972;175:720–31.
Lombard J. Once upon a time the cell membranes: 175 years of cell boundary research. Biol Direct. 2014;9:32.
The authors also acknowledge the financial support from Indian government. WT was supported by a fellowship from the DST-INSPIRE, Government of India. VP was supported by a fellowship from Department of Biotechnology, Government of India.
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Tyagi, W., Pandey, V. & Pokharel, Y.R. Membrane linked RNA glycosylation as new trend to envision epi-transcriptome epoch. Cancer Gene Ther 30, 641–646 (2023). https://doi.org/10.1038/s41417-022-00430-z
This article is cited by
Nature Biotechnology (2023)