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mRNA and snRNA Cap Analogs: Synthesis and Applications

Part of the RNA Technologies book series (RNATECHN)

Abstract

Almost all eukaryotic mRNAs have a monomethylguanosine cap structure consisting of 7-methyl guanosine that is connected via 5′–5′ triphosphate bond to the next nucleoside (m7GpppN; MMG-cap) on their 5′ termini. In unicellular kinetoplastida, including Leishmanias (responsible for a wide spectrum of diseases), the cap is unusually highly methylated (m7Gpppm3 6,6,2′Apm2′Apm2′Cpm2 3,2′U), known as cap-4, while in nematodes (e.g., C. elegans or Ascaris), the mRNA cap is ended with trimethylguanosine (m3 2,2,7GpppN; TMG-cap). A large class of uridine-rich small nuclear RNAs (U snRNAs) on their 5′ termini have also TMG-cap.

Over the last three decades several classes of 5′ mRNA cap analogs, including the natural ones (MMG-cap, TMG-cap, cap-4), have been synthesized in our lab and by other groups. They were serving as valuable tools in elucidating molecular mechanisms of such cap-regulated cellular processes as protein translation initiation, pre-mRNA splicing, RNA intracellular transport, mRNA turnover, and cap-dependent translation inhibition by microRNAs. Some of the synthetic cap dinucleotides (anti-reverse cap analogs; ARCAs), adopted to construct mRNA transcripts with the increased translational efficiency, have found commercial application in production of proteins. In this chapter, we describe the strategies and technical approaches in the synthesis of natural and modified cap analogs. Their application in biology and more recently, in medical studies is also reviewed.

Keywords

  • 5′ mRNA cap
  • Trimethylguanosine cap
  • cap-4
  • Capped oligonucleotides
  • Anti-reverse cap analogs
  • Non-hydrolyzable synthetic cap analogs
  • Cap-binding proteins
  • Capping enzymes
  • Decapping enzymes
  • Translation inhibitors
  • Antitumor mRNA vaccines

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Acknowledgements

This work was supported by grants from the Ministry of Science and Higher Education (Poland) N 301 096 339, National Science Centre (Poland) UMO-2012/07/B/NZ1/00118 and UMO-2013/08/A/NZ1/00866, and National Center of Research and Development (02/EuroNanoMed/2011).

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Correspondence to Edward Darzynkiewicz .

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This article is dedicated to the memory of Aaron Shatkin (1934–2012), the discoverer of the cap structure, my mentor and close friend (E. Darzynkiewicz)

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Stepinski, J., Darzynkiewicz, E. (2014). mRNA and snRNA Cap Analogs: Synthesis and Applications. In: Erdmann, V., Markiewicz, W., Barciszewski, J. (eds) Chemical Biology of Nucleic Acids. RNA Technologies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54452-1_28

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