Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

The principles of guiding by RNA: chimeric RNA–protein enzymes

Nature Reviews Genetics volume 7, pages 475–482 (2006)Cite this article

Abstract

The non-protein-coding transcriptional output of the cell is far greater than previously thought. Although the functions, if any, of the vast majority of these RNA transcripts remain elusive, out of those for which functions have already been established, most act as RNA guides for protein enzymes. Common features of these RNAs provide clues about the evolutionary constraints that led to the development of RNA-guided proteins and the specific biological environments in which target specificity and diversity are most crucial to the cell.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The concept of RNA guiding.
Figure 2: Pairing of a H/ACA snoRNA with an rRNA site for pseudouridine formation.
Figure 3: A putative model of RNA-guided and protein-only enzyme evolution.

Similar content being viewed by others

References

  1. Halic, M. & Beckmann, R. The signal recognition particle and its interactions during protein targeting. Curr. Opin. Struct. Biol. 15, 116–125 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Halic, M. et al. Structure of the signal recognition particle interacting with the elongation-arrested ribosome. Nature 427, 808–814 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Yang, Z., Zhu, Q., Luo, K. & Zhou, Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 414, 317–322 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Wassarman, K. M. & Storz, G. 6S RNA regulates E. coli RNA polymerase activity. Cell 101, 613–623 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Dubey, A. K., Baker, C. S., Romeo, T. & Babitzke, P. RNA sequence and secondary structure participate in high-affinity CsrA–RNA interaction. RNA 11, 1579–1587 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pauler, F. M., Stricker, S. H., Warczok, K. E. & Barlow, D. P. Long-range DNase I hypersensitivity mapping reveals the imprinted Igf2r and Air promoters share cis-regulatory elements. Genome Res. 15, 1379–1387 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Blackburn, E. H. Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett. 579, 859–862 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Meister, G. & Tuschl, T. Mechanisms of gene silencing by double-stranded RNA. Nature 431, 343–349 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Filipowicz, W. RNAi: the nuts and bolts of the RISC machine. Cell 122, 17–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Tomari, Y. & Zamore, P. D. Perspective: machines for RNAi. Genes Dev. 19, 517–529 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Pillai, R. S., Artus, C. G. & Filipowicz, W. Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. RNA 10, 1518–1525 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Farh, K. K. et al. The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 310, 1817–1821 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Bachellerie, J. P., Cavaille, J. & Huttenhofer, A. The expanding snoRNA world. Biochimie 84, 775–790 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Kiss, T. Small nucleolar RNAs: an abundant group of noncoding RNAs with diverse cellular functions. Cell 109, 145–148 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Blum, B., Bakalara, N. & Simpson, L. A model for RNA editing in kinetoplastid mitochondria: 'guide' RNA molecules transcribed from maxicircle DNA provide the edited information. Cell 60, 189–198 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Stuart, K. D., Schnaufer, A., Ernst, N. L. & Panigrahi, A. K. Complex management: RNA editing in trypanosomes. Trends Biochem. Sci. 30, 97–105 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Kawasaki, H. & Taira, K. Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature 431, 211–217 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Matzke, M. A. & Birchler, J. A. RNAi-mediated pathways in the nucleus. Nature Rev. Genet. 6, 24–35 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297, 1833–1837 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Mochizuki, K. & Gorovsky, M. A. Small RNAs in genome rearrangement in Tetrahymena. Curr. Opin. Genet. Dev. 14, 181–187 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Butcher, S. E. & Brow, D. A. Towards understanding the catalytic core structure of the spliceosome. Biochem. Soc. Trans. 33, 447–449 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Gottesman, S. Micros for microbes: non-coding regulatory RNAs in bacteria. Trends Genet. 21, 399–404 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Zhang, A. et al. Global analysis of small RNA and mRNA targets of Hfq. Mol. Microbiol. 50, 1111–1124 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Geissmann, T. A. & Touati, D. Hfq, a new chaperoning role: binding to messenger RNA determines access for small RNA regulator. EMBO J. 23, 396–405 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hopper, A. K. & Phizicky, E. M. tRNA transfers to the limelight. Genes Dev. 17, 162–180 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Agris, P. F. Decoding the genome: a modified view. Nucleic Acids Res. 32, 223–238 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lehmann, K. A. & Bass, B. L. Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. Biochemistry 39, 12875–12884 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Dragon, F. et al. A large nucleolar U3 ribonucleoprotein required for 18S ribosomal RNA biogenesis. Nature 417, 967–970 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Horton, T. L. & Landweber, L. F. Rewriting the information in DNA: RNA editing in kinetoplastids and myxomycetes. Curr. Opin. Microbiol. 5, 620–626 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Eddy, S. R. Non-coding RNA genes and the modern RNA world. Nature Rev. Genet. 2, 919–929 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Krek, A. et al. Combinatorial microRNA target predictions. Nature Genet. 37, 495–500 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Long, M., Betran, E., Thornton, K. & Wang, W. The origin of new genes: glimpses from the young and old. Nature Rev. Genet. 4, 865–875 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Allen, T. A., Von Kaenel, S., Goodrich, J. A. & Kugel, J. F. The SINE-encoded mouse B2 RNA represses mRNA transcription in response to heat shock. Nature Struct. Mol. Biol. 11, 816–821 (2004).

    Article  CAS  Google Scholar 

  36. Ofengand, J. Ribosomal RNA pseudouridines and pseudouridine synthases. FEBS Lett. 514, 17–25 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Liu, B. & Fournier, M. J. Interference probing of rRNA with snoRNPs: a novel approach for functional mapping of RNA in vivo. RNA 10, 1130–1141 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tang, T. H. et al. Identification of 86 candidates for small non-messenger RNAs from the archaeon Archaeoglobus fulgidus. Proc. Natl Acad. Sci. USA 99, 7536–7541 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dennis, P. P., Omer, A. & Lowe, T. A guided tour: small RNA function in Archaea. Mol. Microbiol. 40, 509–519 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Renalier, M. H., Joseph, N., Gaspin, C., Thebault, P. & Mougin, A. The Cm56 tRNA modification in Archaea is catalyzed either by a specific 2′-O-methylase, or a C/D sRNP. RNA 11, 1051–1063 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ma, X. et al. Pseudouridylation of yeast U2 snRNA is catalyzed by either an RNA-guided or RNA-independent mechanism. EMBO J. 24, 2403–2413 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lapeyre, B. & Purushothaman, S. K. Spb1p-directed formation of Gm2922 in the ribosome catalytic center occurs at a late processing stage. Mol. Cell 16, 663–669 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Kirsebom, L. A. RNase P — a 'Scarlet Pimpernel'. Mol. Microbiol. 17, 411–420 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Noller, H. F., Hoffarth, V. & Zimniak, L. Unusual resistance of peptidyl transferase to protein extraction procedures. Science 256, 1416–1419 (1992).

    Article  CAS  PubMed  Google Scholar 

  45. Nissen, P., Hansen, J., Ban, N., Moore, P. B. & Steitz, T. A. The structural basis of ribosome activity in peptide bond synthesis. Science 289, 920–930 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Polacek, N. & Mankin, A. S. The ribosomal peptidyl transferase center: structure, function, evolution, inhibition. Crit. Rev. Biochem. Mol. Biol. 40, 285–311 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Tran, E., Brown, J. & Maxwell, E. S. Evolutionary origins of the RNA-guided nucleotide-modification complexes: from the primitive translation apparatus? Trends Biochem. Sci. 29, 343–350 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Deng, W. et al. Organization of the Caenorhabditis elegans small non-coding transcriptome: genomic features, biogenesis, and expression. Genome Res. 16, 20–29 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huttenhofer, A., Brosius, J. & Bachellerie, J. P. RNomics: identification and function of small, non-messenger RNAs. Curr. Opin. Chem. Biol. 6, 835–843 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Tang, T. H. et al. Identification of novel non-coding RNAs as potential antisense regulators in the archaeon Sulfolobus solfataricus. Mol. Microbiol. 55, 469–481 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Zago, M. A., Dennis, P. P. & Omer, A. D. The expanding world of small RNAs in the hyperthermophilic archaeon Sulfolobus solfataricus. Mol Microbiol. 55, 1812–1828 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Doudna, J. A. & Cech, T. R. The chemical repertoire of natural ribozymes. Nature 418, 222–228 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Doudna, J. A. & Rath, V. L. Structure and function of the eukaryotic ribosome: the next frontier. Cell 109, 153–156 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Storz, G., Altuvia, S. & Wassarman, K. M. An abundance of RNA regulators. Annu. Rev. Biochem. 74, 199–217 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Hastings, M. L., Ingle, H. A., Lazar, M. A. & Munroe, S. H. Post-transcriptional regulation of thyroid hormone receptor expression by cis-acting sequences and a naturally occurring antisense RNA. J. Biol. Chem. 275, 11507–11513 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Nordstrom, K. Plasmid R1 — replication and its control. Plasmid 55, 1–26 (2006).

    Article  PubMed  CAS  Google Scholar 

  57. Ambros, V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 113, 673–676 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Chan, S. W. et al. RNA silencing genes control de novo DNA methylation. Science 303, 1336 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Aravin, A. A. et al. The small RNA profile during Drosophila melanogaster development. Dev. Cell 5, 337–350 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Reinhart, B. J. & Bartel, D. P. Small RNAs correspond to centromere heterochromatic repeats. Science 297, 1831 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Cam, H. P. et al. Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. Nature Genet. 37, 809–819 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Decatur, W. A. & Fournier, M. J. RNA-guided nucleotide modification of ribosomal and other RNAs. J. Biol. Chem. 278, 695–698 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Dominski, Z. & Marzluff, W. F. Formation of the 3′ end of histone mRNA. Gene 239, 1–14 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Marzluff, W. F. Metazoan replication-dependent histone mRNAs: a distinct set of RNA polymerase II transcripts. Curr. Opin. Cell Biol. 17, 274–280 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Nusinow, D. A. & Panning, B. Recognition and modification of sex chromosomes. Curr. Opin. Genet. Dev. 15, 206–213 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Chow, J. C., Yen, Z., Ziesche, S. M. & Brown, C. J. Silencing of the mammalian X chromosome. Annu. Rev. Genomics Hum. Genet. 6, 69–92 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Guthrie, C. & Patterson, B. Spliceosomal snRNAs. Annu. Rev. Genet. 22, 387–419 (1998).

    Article  Google Scholar 

  69. Sharp, P. A. The discovery of split genes and RNA splicing. Trends Biochem. Sci. 30, 279–281 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Ofengand, J. & Fournier, M. J. in Modification and Editing of RNA (eds Grosjean, H. & Benne, R.) Ch. 12 (American Society for Microbiology Press, Washington DC, 1998).

    Google Scholar 

Download references

Acknowledgements

We would like to thank S. Eddy for helpful comments and suggestions and D. Bartel, V. Ambros, R. Bock, M. Terns, L.A. Huber, P. Loidl, N. Polacek and laboratory members from the Division of Genomics and RNomics for critical reading of the manuscript. The work discussed here was supported by an Austrian FWF (Fonds zur Förderung der wissenschaftlichen Forschung) and a German DFG (Deutsche Forschungsgemeinschaft) grant to A.H.

Author information

Authors and Affiliations

  1. Innsbruck Biocenter, Medical University Innsbruck, Fritz-Pregl-Strasse 3, Innsbruck, 6020, Austria

    Alexander Hüttenhofer

  2. Department of Biomolecular Engineering, University of California, Santa Cruz, 1156 High Street, Santa Cruz, 95060, California, USA

    Peter Schattner

Authors
  1. Alexander Hüttenhofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Schattner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Hüttenhofer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Division of Genomics and RNomics, Innsbruck Biocenter

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hüttenhofer, A., Schattner, P. The principles of guiding by RNA: chimeric RNA–protein enzymes. Nat Rev Genet 7, 475–482 (2006). https://doi.org/10.1038/nrg1855

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1855

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing