It was long believed that viral and eukaryotic mRNA molecules are capped at their 5' end solely by the N7-methylguanosine cap, which regulates various aspects of the RNA life cycle, from its biogenesis to its decay. However, the recent discovery of a variety of non-canonical RNA caps derived from metabolites and cofactors - such as NAD, FAD, CoA, UDP-glucose, UDP-N-acetylglucosamine, and dinucleoside polyphosphates - has expanded the known repertoire of RNA modifications. These non-canonical caps are found across all domains of life and can impact multiple aspects of RNA metabolism, including stability, translation initiation, and cellular stress responses. The study of these modifications has been facilitated by sophisticated methodologies such as liquid chromatography-mass spectrometry, which have unveiled their presence in both prokaryotic and eukaryotic organisms. The identification of these novel RNA caps highlights the need for advanced sequencing techniques to characterize the specific RNA types bearing these modifications and understand their roles in cellular processes. Unravelling the biological role of non-canonical RNA caps will provide insights into their contributions to gene expression, cellular adaptation, and evolutionary diversity. This review emphasizes the importance of these technological advancements in uncovering the complete spectrum of RNA modifications and their implications for living systems.

Charles University Faculty of Science Department of Cell Biology Vinicna 7 Prague 2 Czech Republic

Chemical Biology of Nucleic Acids Institute of Organic Chemistry and Biochemistry of the CAS Flemingovo náměstí 2 Prague 6 Czech Republic

Zobrazit více v PubMed

Cappannini A., Ray A., Purta E., Mukherjee S., Boccaletto P., Moafinejad S. N., Lechner A., Barchet C., Klaholz B. P., Stefaniak F., Bujnicki J. M., Nucleic Acids Res. 2024, 52, D239–D244. PubMed PMC

Desrosiers R., Friderici K., Rottman F., Proc. Natl. Acad. Sci. U. S. A. 1974, 71, 3971. PubMed PMC

Amos H., Korn M., Biochim. Biophys. Acta 1958, 29, 444–445. PubMed

Perry R. P., Kelley D. E., LaTorre J., J. Mol. Biol. 1974, 82, 315–331. PubMed

Wei C. M., Gershowitz A., Moss B., Cell 1975, 4, 379–386. PubMed

COHN W. E., J. Biol. Chem. 1960, 235, 1488–1498. PubMed

Topisirovic I., Svitkin Y. V., Sonenberg N., Shatkin A. J., Wiley Interdiscip. Rev. RNA 2011, 2, 277–298. PubMed

Shatkin A. J., Manley J. L., Nat. Struct. Biol. 2000, 7, 838–842. PubMed

Shatkin A. J., Cell 1976, 9, 645–653. PubMed

Furuichi Y., LaFiandra A., Shatkin A. J., Nature 1977, 266, 235–239. PubMed

Wei C. M., Moss B., Proc. Natl. Acad. Sci. U. S. A. 1975, 72, 318. PubMed PMC

Moss B., Gershowitz A., Wei C. M., Boone R., Virology 1976, 72, 341–351. PubMed

Furuichi Y., Shatkin A. J., Adv. Virus Res. 2000, 55, 135. PubMed PMC

Malygin A. G., Shemyakin M. F., FEBS Lett. 1979, 102, 51–54. PubMed

Huang F., Nucleic Acids Res. 2003, 31, e8. PubMed PMC

Julius C., Yuzenkova Y., Nucleic Acids Res. 2017, 45, 8282. PubMed PMC

Chen Y. G., Kowtoniuk W. E., Agarwal I., Shen Y., Liu D. R., Nat. Chem. Biol. 2009, 5, 879. PubMed PMC

Kowtoniuk W. E., Shen Y., Heemstra J. M., Agarwal I., Liu D. R., Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 7768. PubMed PMC

Wang J., Alvin Chew B. L., Lai Y., Dong H., Xu L., Balamkundu S., Cai W. M., Cui L., Liu C. F., Fu X. Y., Lin Z., Shi P. Y., Lu T. K., Luo D., Jaffrey S. R., Dedon P. C., Nucleic Acids Res. 2019, 47, e130. PubMed PMC

Sherwood A. V., Rivera-Rangel L. R., Ryberg L. A., Larsen H. S., Anker K. M., Costa R., Vågbø C. B., Jakljevič E., Pham L. V., Fernandez-Antunez C., Indrisiunaite G., Podolska-Charlery A., Grothen J. E. R., Langvad N. W., Fossat N., Offersgaard A., Al-Chaer A., Nielsen L., Kuśnierczyk A., Sølund C., Weis N., Gottwein J. M., Holmbeck K., Bottaro S., Ramirez S., Bukh J., Scheel T. K. H., Vinther J., Nature 2023, 619, 811–818. PubMed PMC

Doamekpor S. K., Grudzien-Nogalska E., Mlynarska-Cieslak A., Kowalska J., Kiledjian M., Tong L., Nucleic Acids Res. 2020, 48, 6136. PubMed PMC

Luciano D. J., Levenson-Palmer R., Belasco J. G., Mol. Cell 2019, 75, 957–966.e8. PubMed PMC

O. Hudeček, R. Benoni, M. Culka, M. Hubálek, L. Rulíšek, J. Cvačka, H. Cahová, bioRxiv 2019, 563817.

František Potužník J., Nešuta O., Škríba A., Voleníková B., Mititelu M. B., Mancini F., Serianni V., Fernandez H., Spustová K., Trylčová J., Vopalensky P., Cahová H., Angew. Chem. Int. Ed. 2024, 63, e202314951. PubMed

Weixler L., Schäringer K., Momoh J., Lüscher B., Feijs K. L. H., Zaja R., Nucleic Acids Res. 2021, 49, 3634. PubMed PMC

Groslambert J., Prokhorova E., Ahel I., DNA Repair (Amst.) 2021, 105, 103144. PubMed PMC

Munnur D., Bartlett E., Mikolčević P., Kirby I. T., Rack J. G. M., Mikoč A., Cohen M. S., Ahel I., Nucleic Acids Res. 2019, 47, 5658. PubMed PMC

Munir A., Banerjee A., Shuman S., Nucleic Acids Res. 2018, 46, 9617. PubMed PMC

Weixler L., Feijs K. L. H., Zaja R., Nucleic Acids Res. 2022, 50, 9426. PubMed PMC

Wolfram-Schauerte M., Pozhydaieva N., Grawenhoff J., Welp L. M., Silbern I., Wulf A., Billau F. A., Glatter T., Urlaub H., Jäschke A., Höfer K., Nature 2023, 620, 1054–1062. PubMed PMC

Cahová H., Winz M. L., Höfer K., Nübel G., Jäschke A., Nature 2014, 519, 374–377. PubMed

Walters R. W., Matheny T., Mizoue L. S., Rao B. S., Muhlrad D., Parker R., Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 480–485. PubMed PMC

Jiao X., Doamekpor S. K., Bird J. G., Nickels B. E., Tong L., Hart R. P., Kiledjian M., Cell 2017, 168, 1015. PubMed PMC

Wang Y., Li S., Zhao Y., You C., Le B., Gong Z., Mo B., Xia Y., Chen X., Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 12094–12102. PubMed PMC

Zhang H., Zhong H., Zhang S., Shao X., Ni M., Cai Z., Chen X., Xia Y., Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 12072–12077. PubMed PMC

Gomes-Filho J. V., Breuer R., Morales-Filloy H. G., Pozhydaieva N., Borst A., Paczia N., Soppa J., Höfer K., Jäschke A., Randau L., Nat. Commun. 2023, 14, 1–12. PubMed PMC

O. Ruiz-Larrabeiti, R. Benoni, V. Zemlianski, N. Hanišáková, M. Schwarz, B. Brezovská, B. Benoni, J. Hnilicová, V. R. Kaberdin, H. Cahová, M. Vítězová, M. Převorovský, L. Krásný, bioRxiv 2021, 2021.12.14.472595.

Bird J. G., Zhang Y., Tian Y., Panova N., Barvík I., Greene L., Liu M., Buckley B., Krásný L., Lee J. K., Kaplan C. D., Ebright R. H., Nickels B. E., Nature 2016, 535, 444. PubMed PMC

Bird J. G., Basu U., Kuster D., Ramachandran A., Grudzien-Nogalska E., Towheed A., Wallace D. C., Kiledjian M., Temiakov D., Patel S. S., Ebright R. H., Nickels B. E., Elife 2018, 7, DOI 10.7554/ELIFE.42179. PubMed DOI PMC

Yu X., Willmann M. R., Vandivier L. E., Trefely S., Kramer M. C., Shapiro J., Guo R., Lyons E., Snyder N. W., Gregory B. D., Dev Cell 2021, 56, 125. PubMed PMC

Sharma S., Yang J., Favate J., Shah P., Kiledjian M., Commun. Biol. 2023, 6, 1–14. PubMed PMC

Höfer K., Li S., Abele F., Frindert J., Schlotthauer J., Grawenhoff J., Du J., Patel D. J., Jäschke A., Nat. Chem. Biol. 2016, 12, 730. PubMed PMC

Zhang D., Liu Y., Wang Q., Guan Z., Wang J., Liu J., Zou T., Yin P., Cell Res. 2016, 26, 1062–1066. PubMed PMC

Zhang Y., Kuster D., Schmidt T., Kirrmaier D., Nübel G., Ibberson D., Benes V., Hombauer H., Knop M., Jäschke A., Nat. Commun. 2020, 11, 1–17. PubMed PMC

Grudzien-Nogalska E., Wu Y., Jiao X., Cui H., Mateyak M. K., Hart R. P., Tong L., Kiledjian M., Nat Chem Biol 2019, 15, 575. PubMed PMC

Sharma S., Grudzien-Nogalska E., Hamilton K., Jiao X., Yang J., Tong L., Kiledjian M., Nucleic Acids Res. 2020, 48, 6788–6798. PubMed PMC

Kiledjian M., Trends Cell Biol. 2018, 28, 454. PubMed PMC

Doamekpor S. K., Gozdek A., Kwasnik A., Kufel J., Tong L., Nucleic Acids Res. 2020, 48, 349–358. PubMed PMC

Pan S., en Li K., Huang W., Zhong H., Wu H., Wang Y., Zhang H., Cai Z., Guo H., Chen X., Xia Y., J. Integr. Plant Biol. 2020, 62, 967–983. PubMed PMC

Kwasnik A., Wang V. Y. F., Krzyszton M. M., Gozdek A., Zakrzewska-Placzek M., Stepniak K., Poznanski J., Tong L., Kufel J., Nucleic Acids Res. 2019, 47, 4751–4764. PubMed PMC

Mititelu M. B., Hudeček O., Gozdek A., Benoni R., Nešuta O., Krasnodębski S., Kufel J., Cahová H., RSC Chem. Biol. 2023, 4, 223–228. PubMed PMC

Hudeček O., Benoni R., Reyes-Gutierrez P. E., Culka M., Šanderová H., Hubálek M., Rulíšek L., Cvačka J., Krásný L., Cahová H., Nat. Commun. 2020, 11, 1–11. PubMed PMC

Abele F., Höfer K., Bernhard P., Grawenhoff J., Seidel M., Krause A., Kopf S., Schröter M., Jäschke A., Biomolecules 2020, 10, DOI 10.3390/BIOM10040513. PubMed DOI PMC

Wang X., Yu D., Yu J., Hu H., Hang R., Amador Z., Chen Q., Chai J., Chen X., Nat. Commun. 2024, 15, DOI 10.1038/S41467-024-46499-Y. PubMed DOI PMC

Sharma S., Yang J., Grudzien-Nogalska E., Shivas J., Kwan K. Y., Kiledjian M., Nat. Commun. 2022, 13, DOI 10.1038/S41467-022-28555-7. PubMed DOI PMC

Sharma S., Yang J., Doamekpor S. K., Grudizen-Nogalska E., Tong L., Kiledjian M., Nucleic Acids Res. 2022, 50, 8807–8817. PubMed PMC

Ghodge S. V., Raushel F. M., Biochemistry 2015, 54, 2911–2918. PubMed

Jain C., Nucleic Acids Res. 2020, 48, 5616–5623. PubMed PMC

Potužník J. F., Cahova H., RNA Biol. 2024, 21, 1–13. PubMed PMC

Frindert J., Zhang Y., Nübel G., Kahloon M., Kolmar L., Hotz-Wagenblatt A., Burhenne J., Haefeli W. E., Jäschke A., Cell Rep. 2018, 24, 1890–1901.e8. PubMed

Benoni B., Potužník J. F., Škríba A., Benoni R., Trylcova J., Tulpa M., Spustová K., Grab K., Mititelu M.-B., Pačes J., Weber J., Stanek D., Kowalska J., Bednarova L., Keckesova Z., Vopalensky P., Gahurova L., Cahova H., ACS Chem. Biol. 2024, 19, 1243–1249. PubMed PMC

VanBogelen R. A., Kelley P. M., Neidhardt F. C., J. Bacteriol. 1987, 169, 26. PubMed PMC

A. G. McLennan, Ap4A and Other Dinucleoside Polyphosphates 2020, DOI 10.1201/9781003068402/AP4A-DINUCLEOSIDE-POLYPHOSPHATES-ALEXANDER-MCLENNAN.

Grudzien-Nogalska E., Bird J. G., Nickels B. E., Kiledjian M., RNA 2018, 24, 1418. PubMed PMC

Vvedenskaya I. O., Bird J. G., Zhang Y., Zhang Y., Jiao X., Barvík I., Krásný L., Kiledjian M., Taylor D. M., Ebright R. H., Nickels B. E., Mol. Cell 2018, 70, 553. PubMed PMC

Löcherer C., Bühler N., Lafrenz P., Jäschke A., Noncoding RNA 2022, 8, DOI 10.3390/NCRNA8040046/S1. PubMed DOI PMC

Goosen R., Strauss E., RSC Adv. 2017, 7, 19717–19724.

Tsuchiya Y., Pham U., Gout I., Biochem. Soc. Trans 2014, 42, 1107–1111. PubMed

Jones A. E., Arias N. J., Acevedo A., Reddy S. T., Divakaruni A. S., Meriwether D., Metabolites 2021, 11, DOI 10.3390/METABO11080468/S1. PubMed DOI PMC

Bochner B. R., Lee P. C., Wilson S. W., Cutler C. W., Ames B. N., Cell 1984, 37, 225–232. PubMed

Coste H., Brevet A., Plateau P., Blanquet S., J. Biol. Chem. 1987, 262, 12096–12103. PubMed

Plateau P., Fromant M., Kepes F., Blanquet S., J. Bacteriol. 1987, 169, 419–422. PubMed PMC

Celesnik H., Deana A., Belasco J. G., Mol. Cell 2007, 27, 79–90. PubMed PMC

Luciano D. J., Belasco J. G., Methods 2019, 155, 3–9. PubMed PMC

Igloi G. L., Kössel H., Nucleic Acids Res. 1985, 13, 6881–6898. PubMed PMC

Möhler M., Jäschke A., Acc. Chem. Res. 2023, 56, 3000. PubMed PMC

Walseth T. F., Lee H. C., Biochim. Biophys. Acta (BBA) – Mol. Cell Res. 1993, 1178, 235–242. PubMed

Preugschat F., Tomberlin G. H., Porter D. J. T., Arch. Biochem. Biophys. 2008, 479, 114–120. PubMed

V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. Engl. 2002, 41, 2596–2599. PubMed

Tornøe C. W., Christensen C., Meldal M., J. Org. Chem. 2002, 67, 3057–3064. PubMed

Opdyke J. A., Fozo E. M., Hemm M. R., Storz G., J. Mol. Biol. 2011, 406, 29–43. PubMed PMC

D'Alessio G., Josse J., J. Biol. Chem. 1971, 246, 4319–4325. PubMed

Opdyke J. A., Kang J. G., Storz G., J. Bacteriol. 2004, 186, 6698–6705. PubMed PMC

Masuda N., Church G. M., Mol. Microbiol. 2003, 48, 699–712. PubMed

Jin Y., Watt R. M., Danchin A., Huang J. D., BMC Genomics 2009, 10, 165. PubMed PMC

Hayes E. T., Wilks J. C., Sanfilippo P., Yohannes E., Tate D. P., Jones B. D., Radmacher M. D., BonDurant S. S., Slonczewski J. L., BMC Microbiol. 2006, 6, 89. PubMed PMC

Gustavsson N., Diez A. A., Nyström T., Mol. Microbiol. 2002, 43, 107–117. PubMed

Xiang S., Cooper-Morgan A., Jiao X., Kiledjian M., Manley J. L., Tong L., Nature 2009, 458, 784–788. PubMed PMC

Jiao X., Xiang S., Oh C., Martin C. E., Tong L., Kiledjian M., Nature 2010, 467, 608–611. PubMed PMC

Ray A., Frick D. N., Anal. Biochem. 2020, 595, 113622. PubMed PMC

Zhou W., Guan Z., Zhao F., Ye Y., Yang F., Yin P., Zhang D., RNA Biol. 2021, 18, 244. PubMed PMC

Zhang H., Zhong H., Wang X., Zhang S., Shao X., Hu H., Yu Z., Cai Z., Chen X., Xia Y., Proc. Natl. Acad. Sci. U. S. A. 2021, 118, 2026183118. PubMed PMC

Hu H., Flynn N., Zhang H., You C., Hang R., Wang X., Zhong H., Chan Z., Xia Y., Chen X., Proc. Natl. Acad. Sci. U. S. A. 2021, 118, 2025595118. PubMed PMC

Wulf M. G., Buswell J., Chan S. H., Dai N., Marks K., Martin E. R., Tzertzinis G., Whipple J. M., Corrêa I. R., Schildkraut I., Sci. Rep. 2019, 9, 1–9. PubMed PMC

Couttet P., Fromont-Racine M., Steel D., Pictet R., Grange T., Proc. Natl. Acad. Sci. 1997, 94, 5628–5633. PubMed PMC

Niu K., Zhang J., Ge S., Li D., Sun K., You Y., Qiu J., Wang K., Wang X., Liu R., Liu Y., Li B., Zhu Z. J., Qu L., Jiang H., Liu N., Nucleic Acids Res. 2023, 51, e12–e12. PubMed PMC

Ge S., Wang X., Wang Y., Dong M., Li D., Niu K., Wang T., Liu R., Zhao C., Liu N., Zhong M., iScience 2024, 27, 108618. PubMed PMC

Shao X., Zhang H., Zhu Z., Ji F., He Z., Yang Z., Xia Y., Cai Z., Anal. Chem. 2023, 95, 11124–11131. PubMed PMC

Ravasco J. M. J. M., Faustino H., Trindade A., Gois P. M. P., Chem.– A Eur. J. 2019, 25, 43–59. PubMed

Kimura S., Dedon P. C., Waldor M. K., Nat. Chem. Biol. 2020, 16, 964–972. PubMed PMC

Vinther J., Anal. Chem. 2024, 96, 606–609. PubMed PMC

Shao X., Zhang H., Zhu Z., Ji F., He Z., Yang Z., Xia Y., Cai Z., Anal. Chem. 2024, 96, 610–613. PubMed

Maruta T., Yoshimoto T., Ito D., Ogawa T., Tamoi M., Yoshimura K., Shigeoka S., Plant Cell Physiol. 2012, 53, 1106–1116. PubMed

Möhler M., Höfer K., Jäschke A., Molecules 2020, 25, 5492. PubMed PMC

Vilfan I. D., Tsai Y. C., Clark T. A., Wegener J., Dai Q., Yi C., Pan T., Turner S. W., Korlach J., J. Nanobiotechnol. 2013, 11, 1–11. PubMed PMC

Kietrys A. M., Velema W. A., Kool E. T., J. Am. Chem. Soc. 2017, 139, 17074–17081. PubMed PMC

Werner S., Schmidt L., Marchand V., Kemmer T., Falschlunger C., Sednev M. V., Bec G., Ennifar E., Höbartner C., Micura R., Motorin Y., Hildebrandt A., Helm M., Nucleic Acids Res. 2020, 48, 3734. PubMed PMC

Topisirovic I., Sonenberg N., Cold Spring Harb. Symp. Quant. Biol. 2011, 76, 355–367. PubMed

Cole M. D., Cowling V. H., Oncogene 2009, 28, 1169. PubMed PMC

Sonenberg N., Hinnebusch A. G., Cell 2009, 136, 731. PubMed PMC

Decroly E., Ferron F., Lescar J., Canard B., Nat. Rev. Microbiol. 2011, 10, 51–65. PubMed PMC

Kikkert M., J. Innate Immun. 2020, 12, 4–20. PubMed PMC

García-Sastre A., Virus Res. 2011, 162, 12–18. PubMed PMC