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.

  • Review Article
  • Published:

RNA interference: listening to the sound of silence

Abstract

The term RNA interference (RNAi) describes the use of double-stranded RNA to target specific mRNAs for degradation, thereby silencing their expression. RNAi is one manifestation of a broad class of RNA silencing phenomena that are found in plants, animals and fungi. The discovery of RNAi has changed our understanding of how cells guard their genomes, led to the development of new strategies for blocking gene function, and may yet yield RNA-based drugs to treat human disease.

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

Access options

Buy this article

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

Figure 1: A model for the RNAi pathway.
Figure 2: Post-transcriptional gene silencing phenomena.

Similar content being viewed by others

References

  1. Guo, S. & Kemphues, K.J. par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell 81, 611–620 (1995).

    Article  CAS  Google Scholar 

  2. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    CAS  Google Scholar 

  3. Montgomery, M.K., Xu, S. & Fire, A. RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 95, 15502–15507 (1998).

    Article  CAS  Google Scholar 

  4. Hammond, S.M., Bernstein, E., Beach, D. & Hannon, G.J. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 404, 293–296 (2000).

    Article  CAS  Google Scholar 

  5. Zamore, P., Tuschl, T., Sharp, P. & Bartel, D. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101, 25–33 (2000).

    Article  CAS  Google Scholar 

  6. Ketting, R.F. & Plasterk, R.H. A genetic link between co-suppression and RNA interference in C. elegans. Nature 404, 296–298 (2000).

    Article  CAS  Google Scholar 

  7. Ketting, R.F., Haverkamp, T.H., van Luenen, H.G. & Plasterk, R.H. Mut-7 of C. elegans, required for transposon silencing and RNA interference, is a homolog of Werner syndrome helicase and RNaseD. Cell 99, 133–141 (1999).

    Article  CAS  Google Scholar 

  8. Wu-Scharf, D., Jeong, B., Zhang, C. & Cerutti, H. Transgene and transposon silencing in chlamydomonas reinhardtii by a DEAH-Box RNA helicase. Science 290, 1159–1163 (2000).

    Article  CAS  Google Scholar 

  9. Aravin, A.A. et al. Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline. Curr. Biol. 11, 1017–1027 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  10. Gonczy, P. et al. Functional genomic analysis of cell division in C. elegans using RNAi of genes on chromosome III. Nature 408, 331–336 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  11. Fraser, A.G. et al. Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408, 325–330 (2000).

    Article  CAS  Google Scholar 

  12. Kennerdell, J.R. & Carthew, R.W. Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the wingless pathway. Cell 95,1017–1026 (1998).

    Article  CAS  Google Scholar 

  13. Misquitta, L. & Paterson, B.M. Targeted disruption of gene function in Drosophila by RNA interference (RNA-i): a role for nautilus in embryonic somatic muscle formation. Proc. Natl. Acad. Sci. USA 96, 1451–1456 (1999).

    Article  CAS  Google Scholar 

  14. Hughes, C.L. & Kaufman, T.C. RNAi analysis of Deformed, proboscipedia and Sex combs reduced in the milkweed bug Oncopeltus fasciatus: novel roles for Hox genes in the hemipteran head. Development 127, 3683–3694. (2000).

    CAS  PubMed  Google Scholar 

  15. Ngo, H., Tschudi, C., Gull, K. & Ullu, E. Double-stranded RNA induces mRNA degradation in Trypanosoma brucei. Proc. Natl. Acad. Sci. USA 95, 14687–14692 (1998).

    Article  CAS  Google Scholar 

  16. Sánchez-Alvarado, A. & Newmark, P.A. Double-stranded RNA specifically disrupts gene expression during planarian regeneration. Proc. Natl. Acad. Sci. USA 96, 5049–5054 (1999).

    Article  Google Scholar 

  17. Lohmann, J.U., Endl, I. & Bosch, T.C. Silencing of Developmental Genes in Hydra. Dev. Biol. 214, 211–214 (1999).

    Article  CAS  Google Scholar 

  18. Elbashir, S.M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in mammalian cell culture. Nature 411, 494–498 (2001).

    Article  CAS  Google Scholar 

  19. Elbashir, S.M., Lendeckel, W. & Tuschl, T. RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes & Dev. 15, 188–200 (2001).

    Article  CAS  Google Scholar 

  20. Bernstein, E., Caudy, A.A., Hammond, S.M. & Hannon, G.J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363–366 (2001).

    Article  CAS  Google Scholar 

  21. Cogoni, C., Romano, N. & Macino, G. Suppression of gene expression by homologous transgenes. Antonie Van Leeuwenhoek 65, 205–209 (1994).

    Article  CAS  Google Scholar 

  22. Cogoni, C. et al. Transgene silencing of the al-1 gene in vegetative cells of Neurospora is mediated by a cytoplasmic effector and does not depend on DNA–DNA interactions or DNA methylation. EMBO J. 15, 3153–3163 (1996).

    Article  CAS  PubMed Central  Google Scholar 

  23. Aravind, L., Watanabe, H., Lipman, D.J. & Koonin, E.V. Lineage-specific loss and divergence of functionally linked genes in eukaryotes. Proc. Natl. Acad. Sci. USA 97, 11319–11324 (2000).

    Article  CAS  Google Scholar 

  24. Tuschl, T., Zamore, P.D., Lehmann, R., Bartel, D.P. & Sharp, P.A. Targeted mRNA degradation by double-stranded RNA in vitro. Genes & Dev. 13, 3191–3197 (1999).

    Article  CAS  Google Scholar 

  25. Hamilton, A.J. & Baulcombe, D.C. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 286, 950–952 (1999).

    Article  CAS  Google Scholar 

  26. Yang, D., Lu, H. & Erickson, J.W. Evidence that processed small dsRNAs may mediate sequence-specific mRNA degradation during RNAi in Drosophila embryos. Curr. Biol. 10, 1191–1200 (2000).

    Article  CAS  Google Scholar 

  27. Parrish, S., Fleenor, J., Xu, S., Mello, C. & Fire, A. Functional anatomy of a dsRNA trigger. Differential requirement for the two trigger strands in RNA interference. Mol. Cell 6, 1077–1087 (2000).

    Article  CAS  Google Scholar 

  28. Jacobsen, S.E., Running, M.P. & Meyerowitz, E.M. Disruption of an RNA helicase/RNase III gene in Arabidopsis causes unregulated cell division in floral meristems. Development 126, 5231–5243 (1999).

    CAS  PubMed  Google Scholar 

  29. Ray, A., Lang, J.D., Golden, T. & Ray, S. SHORT INTEGUMENT (SIN1), agene required for ovule development in Arabidopsis, also controls flowering time. Development 122, 2631–2638 (1996).

    CAS  PubMed  Google Scholar 

  30. Ray, S., Golden, T. & Ray, A. Maternal effects of the short integument mutation on embryo development in Arabidopsis. Dev. Biol. 180, 365–369 (1996).

    Article  CAS  Google Scholar 

  31. Grishok, A. et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106, 23–34 (2001).

    Article  CAS  Google Scholar 

  32. Hutvágner, G. et al. A cellular function for the RNA-interference enzyme dicer in the maturation of the let-7 small temporal RNA. Science, 293, 834–838 (2001).

    Article  Google Scholar 

  33. Cerutti, L., Mian, N. & Bateman, A. Domains in gene silencing and cell differentiation proteins: the novel PAZ domain and redefinition of the Piwi domain. Trends Biochem. Sci. 481–482 (2000).

  34. Grishok, A., Tabara, H. & Mello, C. Genetic requirements for inheritance of RNAi in C. elegans. Science 287, 2494–2497 (2000).

    Article  CAS  Google Scholar 

  35. Dernburg, A.F., Zalevsky, J., Colaiácovo, M.P. & Villeneuve, A.M. Transgene-mediated cosuppression in the C. elegans germ line. Genes & Dev. 14,1578–1583 (2000).

    CAS  Google Scholar 

  36. Cogoni, C. & Macino, G. Isolation of quelling-defective (qde) mutants impaired in posttranscriptional transgene-induced gene silencing in Neurospora crassa. Proc. Natl. Acad. Sci. USA 94, 10233–10238 (1997).

    Article  CAS  Google Scholar 

  37. Fagard, M., Boutet, S., Morel, J.-B., Bellini, C. & Vaucheret, H. AGO1, QDE-2,and RDE-1 are related proteins required for post-transcriptional gene silencing in plants, quelling in fungi, and RNA interference in animals. Proc. Natl. Acad. Sci. USA 97, 11650–11654 (2000).

    Article  CAS  Google Scholar 

  38. Tabara, H. et al. The rde-1 gene, RNA interference, and transposon silencing in C. elegans. Cell 99, 123–132 (1999).

    Article  CAS  Google Scholar 

  39. Sharp, P.A. & Zamore, P.D. RNA interference. Science 287, 2431–2433 (2000).

    Article  CAS  Google Scholar 

  40. Catalanotto, C., Azzalin, G., Macino, G. & Cogoni, C. Transcription: Gene silencing in worms and fungi. Nature 404, 245 (2000).

    Article  CAS  Google Scholar 

  41. Fire, A. RNA-triggered gene silencing. Trends Genet. 15, 358–363 (1999).

    Article  CAS  Google Scholar 

  42. Cogoni, C. & Macino, G. Gene silencing in Neurospora crassa requires a protein homologous to RNA-dependent RNA polymerase. Nature 399, 166–169 (1999).

    Article  CAS  Google Scholar 

  43. Smardon, A. et al. EGO-1 is related to RNA-directed RNA polymerase and functions in germ-line development and RNA interference in C. elegans. Curr. Biol. 10, 169–178 (2000).

    Article  CAS  Google Scholar 

  44. Dalmay, T., Hamilton, A., Rudd, S., Angell, S. & Baulcombe, D.C. An RNA-dependent RNA polymerase gene in Arabidopsis is required for posttranscriptional gene silencing mediated by a transgene but not by a virus. Cell 101, 543–553 (2000).

    Article  CAS  Google Scholar 

  45. Mourrain, P. et al. Arabidopsis SGS2 and SGS3 genes are required for posttranscriptional gene silencing and natural virus resistance. Cell 101,533–542 (2000).

    Article  CAS  Google Scholar 

  46. Qiao, L. et al. Enhancers of glp-1, a gene required for cell-signaling in Caenorhabditis elegans, define a set of genes required for germline development. Genetics 141, 551–569 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Li, W.X. & Ding, S.W. Viral suppressors of RNA silencing. Curr Opin Biotechnol 12, 150–154 (2001).

    Article  CAS  Google Scholar 

  48. Brigneti, G. et al. Viral pathogenicity determinants are suppressors of transgene silencing in Nicotiana benthamiana. EMBO J. 17, 6739–6746 (1998).

    Article  CAS  PubMed Central  Google Scholar 

  49. Lucy, A.P., Guo, H.S., Li, W.X. & Ding, S.W. Suppression of post-transcriptional gene silencing by a plant viral protein localized in the nucleus. EMBO J. 19,1672–1680 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  50. Llave, C., Kasschau, K.D. & Carrington, J.C. Virus-encoded suppressor of posttranscriptional gene silencing targets a maintenance step in the silencing pathway. Proc. Natl. Acad. Sci. USA 97, 13401–13406 (2000).

    Article  CAS  Google Scholar 

  51. Mallory, A.C. et al. HC-Pro suppression of transgene silencing eliminates the small RNAs but not transgene methylation or the mobile signal. Plant Cell 13,571–583 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  52. Voinnet, O., Lederer, C. & Baulcombe, D.C. A viral movement protein prevents spread of the gene silencing signal in Nicotiana benthamiana. Cell 103, 157–167 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I would like to thank my colleagues for generously sharing their ideas with me, notably D. Bartel, C. Mello, A. Fire, P. Sharp, and T. Tuschl, and I especially thank the members of my own laboratory, with whom it is a great privilege to study RNAi.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zamore, P. RNA interference: listening to the sound of silence. Nat Struct Mol Biol 8, 746–750 (2001). https://doi.org/10.1038/nsb0901-746

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsb0901-746

This article is cited by

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