Nothing Special   »   [go: up one dir, main page]
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.

  • Article
  • Published:

A widespread self-cleaving ribozyme class is revealed by bioinformatics

Nature Chemical Biology volume 10, pages 56–60 (2014)Cite this article

Subjects

Abstract

Ribozymes are noncoding RNAs that promote chemical transformations with rate enhancements approaching those of protein enzymes. Although ribozymes are likely to have been abundant during the RNA world era, only ten classes are known to exist among contemporary organisms. We report the discovery and analysis of an additional self-cleaving ribozyme class, called twister, which is present in many species of bacteria and eukarya. Nearly 2,700 twister ribozymes were identified that conform to a secondary structure consensus that is small yet complex, with three stems conjoined by internal and terminal loops. Two pseudoknots provide tertiary structure contacts that are critical for catalytic activity. The twister ribozyme motif provides another example of a natural RNA catalyst and calls attention to the potentially varied biological roles of this and other classes of widely distributed self-cleaving RNAs.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Consensus sequence and secondary-structure model for twister self-cleaving ribozymes.
Figure 2: Common associations between various genetic elements and twister or hammerhead RNAs.
Figure 3: Sequence, structure and activity of a twister ribozyme from N. vitripennis.
Figure 4: Kinetic characteristics of a twister ribozyme derived from an environmental DNA sequence.

Similar content being viewed by others

References

  1. Cech, T.R. Ribozymes, the first 20 years. Biochem. Soc. Trans. 30, 1162–1166 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Benner, S.A., Ellington, A.D. & Tauer, A. Modern metabolism as a palimpsest of the RNA world. Proc. Natl. Acad. Sci. USA 86, 7054–7058 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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 

  4. 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 35, 849–857 (1983).

    Article  CAS  PubMed  Google Scholar 

  5. Mondragón, A. Structural studies of RNase P. Annu. Rev. Biophys. 42, 537–557 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Kruger, K. et al. Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena. Cell 31, 147–157 (1982).

    Article  CAS  PubMed  Google Scholar 

  7. Peebles, C.L. et al. A self-splicing RNA excises an intron lariat. Cell 44, 213–223 (1986).

    Article  CAS  PubMed  Google Scholar 

  8. Lambowitz, A.M. & Zimmerly, S. Group II introns: mobile ribozymes that invade DNA. Cold Spring Harb. Perspect. Biol. 3, a003616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ferré-D'Amaré, A.R. & Scott, W.G. Small self-cleaving ribozymes. Cold Spring Harb. Perspect. Biol. 2, a003574 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Prody, G.A., Bakos, J.T., Buzayan, J.M., Schneider, I.R. & Bruening, G. Autolytic processing of dimeric plant virus satellite RNA. Science 231, 1577–1580 (1986).

    Article  CAS  PubMed  Google Scholar 

  11. Buzayan, J.M., Gerlach, W.L. & Bruening, G. Non-enzymatic cleavage and ligation of RNAs complementary to a plant virus satellite RNA. Nature 323, 349–353 (1986).

    Article  CAS  Google Scholar 

  12. Sharmeen, L., Kuo, M.Y., Dinter-Gottlieb, G. & Taylor, J. Antigenomic RNA of human hepatitis delta virus can undergo self-cleavage. J. Virol. 62, 2674–2679 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. de la Peña, M. & Garcia-Robles, I. Ubiquitous presence of the hammerhead ribozyme motif along the tree of life. RNA 16, 1943–1950 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jimenez, R.M., Delwart, E. & Luptak, A. Structure-based search reveals hammerhead ribozymes in the human microbiome. J. Biol. Chem. 286, 7737–7743 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Perreault, J. et al. Identification of hammerhead ribozymes in all domains of life reveals novel structural variations. PLoS Comput. Biol. 7, e1002031 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Seehafer, C., Kalweit, A., Steger, G., Gräf, S. & Hammann, C. From alpaca to zebrafish: hammerhead ribozymes wherever you look. RNA 17, 21–26 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Webb, C.H., Riccitelli, N.J., Ruminski, D.J. & Luptak, A. Widespread occurrence of self-cleaving ribozymes. Science 326, 953 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Webb, C.-H.T. & Lupták, A. HDV-like self-cleaving ribozymes. RNA Biol. 8, 719–727 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hammann, C., Luptak, A., Perreault, J. & De La Peña, M. The ubiquitous hammerhead ribozyme. RNA 18, 871–885 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martick, M., Horan, L.H., Noller, H.F. & Scott, W.G. A discontinuous hammerhead ribozyme embedded in a mammalian messenger RNA. Nature 454, 899–902 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hammann, C. & Westhof, E. The unforeseeable hammerhead ribozyme. F1000 Biol. Rep. 1, 6 (2009).

    PubMed  PubMed Central  Google Scholar 

  22. Salehi-Ashtiani, K., Lupták, A., Litovchick, A. & Szostak, J.W. A genome-wide search for ribozymes reveals an HDV-like sequence in the human CPEB3 gene. Science 313, 1788–1792 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Winkler, W.C., Nahvi, A., Roth, A., Collins, J.A. & Breaker, R.R. Control of gene expression by a natural metabolite-responsive ribozyme. Nature 428, 281–286 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. McCown, P.J., Roth, A. & Breaker, R.R. An expanded collection and refined consensus model of glmS ribozymes. RNA 17, 728–736 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. McCarthy, T.J. et al. Ligand requirements for glmS ribozyme self-cleavage. Chem. Biol. 12, 1221–1226 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Klein, D.J. & Ferré-D'Amaré, A.R. Structural basis of glmS ribozyme activation by glucosamine-6-phosphate. Science 313, 1752–1756 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Cochrane, J.C., Lipchock, S.V. & Strobel, S.A. Structural investigation of the glmS ribozyme bound to its catalytic cofactor. Chem. Biol. 14, 97–105 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Williams, K.P., Ciafré, S. & Tocchini-Valentini, G.P. Selection of novel Mg2+-dependent self-cleaving ribozymes. EMBO J. 14, 4551–4557 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tang, J. & Breaker, R.R. Structural diversity of self-cleaving ribozymes. Proc. Natl. Acad. Sci. USA 97, 5784–5789 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weinberg, Z. et al. Comparative genomics reveals 104 candidate structured RNAs from bacteria, archaea, and their metagenomes. Genome Biol. 11, R31 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Breaker, R.R. Prospects for riboswitch discovery and analysis. Mol. Cell 43, 867–879 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Canny, M.D. et al. Fast cleavage kinetics of a natural hammerhead ribozyme. J. Am. Chem. Soc. 126, 10848–10849 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Emilsson, G.M., Nakamura, S., Roth, A. & Breaker, R.R. Ribozyme speed limits. RNA 9, 907–918 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Breaker, R.R. et al. A common speed limit for RNA-cleaving ribozymes and deoxyribozymes. RNA 9, 949–957 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cochrane, J.C. & Strobel, S.A. Catalytic strategies of self-cleaving ribozymes. Acc. Chem. Res. 41, 1027–1035 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Collins, J.A., Irnov, I., Baker, S. & Winkler, W.C. Mechanism of mRNA destabilization by the glmS ribozyme. Genes Dev. 21, 3356–3368 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. DeYoung, M., Siwkowski, A.M., Lian, Y. & Hampel, A. Catalytic properties of hairpin ribozymes derived from Chicory Yellow Mottle Virus and Arabis Mosaic Virus satellite RNAs. Biochemistry 34, 15785–15791 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Saville, B.J. & Collins, R.A. A site-specific self-cleavage reaction performed by a novel RNA in Neurospora mitochondria. Cell 61, 685–696 (1990).

    Article  CAS  PubMed  Google Scholar 

  39. Flores, R. et al. Viroid replication: rolling-circles, enzymes and ribozymes. Viruses 1, 317–334 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Eickbush, D.G. & Eickbush, T.H. R2 retrotransposons encode a self-cleaving ribozyme for processing from an rRNA cotranscript. Mol. Cell. Biol. 30, 3142–3150 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sánchez-Luque, F.J., López, M.C., Macias, F., Alonso, C. & Thomas, M.C. Identification of a hepatitis delta virus–like ribozyme at the mRNA 5′-end of the L1Tc retrotransposon from Trypanosoma cruzi. Nucleic Acids Res. 39, 8065–8077 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ruminski, D.J., Webb, C.-H.T., Riccitelli, N.J. & Lupták, A. Processing and translation initiation of non-long terminal repeat retrotransposons by Hepatitis Delta Virus (HDV)-like self-cleaving ribozymes. J. Biol. Chem. 286, 41286–41295 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee, E.R., Baker, J.L., Weinberg, Z., Sudarsan, N. & Breaker, R.R. An allosteric self-splicing ribozyme triggered by a bacterial second messenger. Science 329, 845–848 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pruitt, K.D., Tatusova, T. & Maglott, D.R. NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 35, D61–D65 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Baker, J.L. et al. Widespread genetic switches and toxicity resistance proteins for fluoride. Science 335, 233–235 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Zytnicki, M., Gaspin, C. & Schiex, T. DARN! A weighted constraint solver for RNA motif localization. Constraints 13, 91–109 (2008).

    Article  Google Scholar 

  47. Markowitz, V.M. et al. IMG/M: a data management and analysis system for metagenomes. Nucleic Acids Res. 36, D534–D538 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Human Microbiome Project Consortium. A framework for human microbiome research. Nature 486, 215–221 (2012).

  49. Hofacker, I.L. RNA secondary structure analysis using the Vienna RNA package. Curr. Protoc. Bioinformatics 26, 12.02 (2009).

    Google Scholar 

  50. Weinberg, Z. & Breaker, R.R. R2R—software to speed the depiction of aesthetic consensus RNA secondary structures. BMC Bioinformatics 12, 3 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhu, W., Lomsadze, A. & Borodovsky, M. Ab initio gene identification in metagenomic sequences. Nucleic Acids Res. 38, e132 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Marchler-Bauer, A. et al. CDD: a conserved domain database for the functional annotation of proteins. Nucleic Acids Res. 39, D225–D229 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Nawrocki, E.P., Kolbe, D.L. & Eddy, S.R. Infernal 1.0: inference of RNA alignments. Bioinformatics 25, 1335–1337 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Roth, A., Nahvi, A., Lee, M., Jona, I. & Breaker, R.R. Characteristics of the glmS ribozyme suggest only structural roles for divalent metal ions. RNA 12, 607–619 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Korbie, D.J. & Mattick, J.S. Touchdown PCR for increased specificity and sensitivity in PCR amplification. Nat. Protoc. 3, 1452–1456 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Murdock for performing the twister ribozyme ligation assay, P. McCown and other members of the Breaker laboratory for helpful discussions, R. Knight for alerting us to useful metagenome data sets, S.L. Tausta and T. Nelson (Yale University) for providing us with rice seeds, and N. Carriero and R. Bjornson for assistance with the Yale Life Sciences High Performance Computing Center (US National Institutes of Health (NIH) grant RR19895-02). This work was supported by the NIH (GM022778) and by the Howard Hughes Medical Institute. P.B.K. was supported by the Gruber Science Fellowship.

Author information

Author notes

  1. Adam Roth & Zasha Weinberg

    Present address: Present address: Phosplatin Therapeutics, New York, New York, USA.,

  2. Tyler D Ames: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, USA

    Adam Roth, Zasha Weinberg, Andy G Y Chen, Peter B Kim, Tyler D Ames & Ronald R Breaker

  2. Howard Hughes Medical Institute, Yale University, New Haven, Connecticut, USA

    Adam Roth, Zasha Weinberg, Tyler D Ames & Ronald R Breaker

  3. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA

    Ronald R Breaker

Authors
  1. Adam Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zasha Weinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andy G Y Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter B Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tyler D Ames
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ronald R Breaker
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Z.W. and T.D.A. conducted the bioinformatics analyses; A.R., A.G.Y.C. and P.B.K. conducted the biochemical and genetic analyses; R.R.B. prepared the manuscript; and all of the authors interpreted data, designed experiments and critically reviewed the text and figures.

Corresponding author

Correspondence to Ronald R Breaker.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–13. This file also contains the legend for Supplementary Data Set 1. (PDF 3774 kb)

Supplementary Data Set 1

This separate file displays the taxa, sequence accession numbers, coordinates, gene neighborhoods and multiple sequence alignments corresponding to the identified twister ribozyme representatives. In additional separate files, alignments of type P1, type P3 and type P5 twister ribozyme sequences are provided individually in Stockholm formats. (PDF 4863 kb)

Supplementary Data Set 2

Type P1 sequence alignment file in Stockholm format. (TXT 457 kb)

Supplementary Data Set 3

Type P3 sequence alignment file in Stockholm format. (TXT 1 kb)

Supplementary Data Set 4

Type P5 sequence alignment file in Stockholm format. (TXT 47 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roth, A., Weinberg, Z., Chen, A. et al. A widespread self-cleaving ribozyme class is revealed by bioinformatics. Nat Chem Biol 10, 56–60 (2014). https://doi.org/10.1038/nchembio.1386

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.1386

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