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  • Review Article
  • Published:

Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?

Nature Reviews Genetics volume 9, pages 102–114 (2008)Cite this article

Key Points

  • MicroRNAs (miRNAs) — approximately 21-nucleotide-long, genome-encoded RNAs — have emerged as key regulators of gene expression in eukaryotes.

  • miRNAs represent just one class of small RNA regulators, the others being small interfering RNAs (siRNAs) and PIWI-associated RNAs (piRNAs), all of which operate in processes that are collectively referred to as RNA silencing.

  • miRNAs control gene expression post-transcriptionallly, by hybridizing to target mRNAs and thereby regulating their translation or stability.

  • By targeting dozens or even hundreds of different mRNAs, individual miRNAs have the potential to fine-tune or modulate the expression of genes that participate in a specific metabolic or developmental pathway; but they can also act as reversible switches to turn on and off mRNA translation.

  • miRNAs function as components of ribonucleoprotein (RNP) complexes, referred to as either miRNPs or miRNA-induced silencing complexes (miRISCs), with proteins of the Argonaute (AGO) family being the most important and best characterized components.

  • Studies performed both in vivo and in cell-free extracts have provided some mechanistic insights into the miRNA-mediated repression, although many details of the repression are still poorly understood.

Abstract

MicroRNAs constitute a large family of small, approximately 21-nucleotide-long, non-coding RNAs that have emerged as key post-transcriptional regulators of gene expression in metazoans and plants. In mammals, microRNAs are predicted to control the activity of approximately 30% of all protein-coding genes, and have been shown to participate in the regulation of almost every cellular process investigated so far. By base pairing to mRNAs, microRNAs mediate translational repression or mRNA degradation. This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of microRNA function.

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Figure 1: Examples of reporters used in studies of microRNA function.
Figure 2: Domain organization of Argonaute and GW182 proteins.
Figure 3: Possible mechanisms of the microRNA-mediated post-transcriptional gene repression in animal cells.
Figure 4: Possible interplay between RNA binding proteins and micro-ribonucleoproteins interacting with the mRNAs 3′ UTR.

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References

  1. Bushati, N. & Cohen, S. M. microRNA functions. Annu. Rev. Cell Dev. Biol. 23, 175–205 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Kloosterman, W. P. & Plasterk, R. H. The diverse functions of microRNAs in animal development and disease. Dev. Cell 11, 441–450 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Rana, T. M. Illuminating the silence: understanding the structure and function of small RNAs. Nature Rev. Mol. Cell Biol. 8, 23–36 (2007).

    Article  CAS  Google Scholar 

  4. Molnar, A., Schwach, F., Studholme, D. J., Thuenemann, E. C. & Baulcombe, D. C. miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii. Nature 447, 1126–1129 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Zhao, T. et al. A complex system of small RNAs in the unicellular green alga Chlamydomonas reinhardtii. Genes Dev. 21, 1190–1203 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Esquela-Kerscher, A. & Slack, F. J. Oncomirs — microRNAs with a role in cancer. Nature Rev. Cancer 6, 259–269 (2006).

    Article  CAS  Google Scholar 

  7. Chang, T. C. & Mendell, J. T. microRNAs in vertebrate physiology and human disease. Annu. Rev. Genomics Hum. Genet. 8, 215–239 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Krutzfeldt, J. & Stoffel, M. microRNAs: a new class of regulatory genes affecting metabolism. Cell Metab. 4, 9–12 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Bao, N., Lye, K. W. & Barton, M. K. MicroRNA binding sites in Arabidopsis class III HD-ZIP mRNAs are required for methylation of the template chromosome. Dev. Cell 7, 653–662 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Valencia-Sanchez, M. A., Liu, J., Hannon, G. J. & Parker, R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20, 515–524 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Pillai, R. S., Bhattacharyya, S. N. & Filipowicz, W. Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol. 17, 118–126 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Standart, N. & Jackson, R. J. MicroRNAs repress translation of m7Gppp-capped target mRNAs in vitro by inhibiting initiation and promoting deadenylation. Genes Dev. 21, 1975–1982 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Jackson, R. J. & Standart, N. How do microRNAs regulate gene expression? Sci. STKE 2007, re1 (2007).

    Article  PubMed  Google Scholar 

  14. Nilsen, T. W. Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet. 23, 243–249 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Hwang, H. W., Wentzel, E. A. & Mendell, J. T. A hexanucleotide element directs microRNA nuclear import. Science 315, 97–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Eulalio, A., Behm-Ansmant, I. & Izaurralde, E. P-bodies: at the crossroads of post-transcriptional pathways. Nature Rev. Mol. Cell Biol. 8, 9–22 (2007).

    Article  CAS  Google Scholar 

  18. Leung, A. K. & Sharp, P. A. Function and localization of microRNAs in mammalian cells. Cold Spring Harb. Symp. Quant. Biol. 71, 29–38 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Sontheimer, E. J. Assembly and function of RNA silencing complexes. Nature Rev. Mol. Cell Biol. 6, 127–138 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Du, T. & Zamore, P. D. microPrimer: the biogenesis and function of microRNA. Development 132, 4645–4652 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Kim, V. N. & Nam, J. W. Genomics of microRNA. Trends Genet. 22, 165–173 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Filipowicz, W., Jaskiewicz, L., Kolb, F. A. & Pillai, R. S. Post-transcriptional gene silencing by siRNAs and miRNAs. Curr. Opin. Struct. Biol. 15, 331–341 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Peters, L. & Meister, G. Argonaute proteins: mediators of RNA silencing. Mol. Cell 26, 611–623 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Tolia, N. H. & Joshua-Tor, L. Slicer and the argonautes. Nature Chem. Biol. 3, 36–43 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. Meister, G. et al. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol. Cell 15, 185–197 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Jones-Rhoades, M. W., Bartel, D. P. & Bartel, B. MicroRNAS and their regulatory roles in plants. Annu. Rev. Plant Biol. 57, 19–53 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Doench, J. G. & Sharp, P. A. Specificity of microRNA target selection in translational repression. Genes Dev. 18, 504–511 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Brennecke, J., Stark, A., Russell, R. B. & Cohen, S. M. Principles of microRNA-target recognition. PLoS Biol. 3, 404–418 (2005).

    Article  CAS  Google Scholar 

  32. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Grimson, A. et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nielsen, C. B. et al. Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. RNA 13, 1894–1910 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lytle, J. R., Yario, T. A. & Steitz, J. A. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc. Natl Acad. Sci. USA 104, 9667–6972 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kloosterman, W. P., Wienholds, E., Ketting, R. F. & Plasterk, R. H. Substrate requirements for let-7 function in the developing zebrafish embryo. Nucleic Acids Res. 32, 6284–6291 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Easow, G., Teleman, A. A. & Cohen, S. M. Isolation of microRNA targets by miRNP immunopurification. RNA 13, 1198–1204 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Merrick, W. C. Cap-dependent and cap-independent translation in eukaryotic systems. Gene 332, 1–11 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Kapp, L. D. & Lorsch, J. R. The molecular mechanics of eukaryotic translation. Annu. Rev. Biochem. 73, 657–704 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Wells, S. E., Hillner, P. E., Vale, R. D. & Sachs, A. B. Circularization of mRNA by eukaryotic translation initiation factors. Mol. Cell 2, 135–140 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Derry, M. C., Yanagiya, A., Martineau, Y. & Sonenberg, N. Regulation of poly(A)-binding protein through PABP-interacting proteins. Cold Spring Harb. Symp. Quant. Biol. 71, 537–543 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Jackson, R. J. Alternative mechanisms of initiating translation of mammalian mRNAs. Biochem. Soc. Trans. 33, 1231–1241 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Pillai, R. S. et al. Inhibition of translational initiation by let-7 microRNA in human cells. Science 309, 1573–1576 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Humphreys, D. T., Westman, B. J., Martin, D. I. & Preiss, T. MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(A) tail function. Proc. Natl Acad. Sci. USA 102, 16961–16966 (2005). This paper and reference 43 provide the first evidence that miRNAs repress translational initiation, probably by interfering with the function of the cap-binding factor eIF4E.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bhattacharyya, S. N., Habermacher, R., Martine, U., Closs, E. I. & Filipowicz, W. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125, 1111–1124 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Chekulaeva, M., Hentze, M. W. & Ephrussi, A. Bruno acts as a dual repressor of oskar translation, promoting mRNA oligomerization and formation of silencing particles. Cell 124, 521–533 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Richter, J. D. & Sonenberg, N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433, 477–480 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Cho, P. F. et al. A new paradigm for translational control: inhibition via 5′–3′ mRNA tethering by Bicoid and the eIF4E cognate 4EHP. Cell 121, 411–423 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Kiriakidou, M. et al. An mRNA m7G cap binding-like motif within human Ago2 represses translation. Cell 129, 1141–1151 (2007). This paper reports that human AGO2 has the potential to directly interact with the m7G cap and to repress translational initiation by competing with eIF4E for cap binding.

    Article  CAS  PubMed  Google Scholar 

  50. Marcotrigiano, J., Gingras, A. C., Sonenberg, N. & Burley, S. K. Cocrystal structure of the messenger RNA 5′ cap-binding protein (eIF4E) bound to 7-methyl-GDP. Cell 89, 951–961 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Doench, J. G., Petersen, C. P. & Sharp, P. A. siRNAs can function as miRNAs. Genes Dev. 17, 438–442 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang, B., Love, T. M., Call, M. E., Doench, J. G. & Novina, C. D. Recapitulation of short RNA-directed translational gene silencing in vitro. Mol. Cell 22, 553–560 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Thermann, R. & Hentze, M. W. Drosophila miR2 induces pseudo-polysomes and inhibits translation initiation. Nature 447, 875–878 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Mathonnet, G. et al. microRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F. Science 317, 1764–1767 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Wakiyama, M., Takimoto, K., Ohara, O. & Yokoyama, S. Let-7 microRNA-mediated mRNA deadenylation and translational repression in a mammalian cell-free system. Genes Dev. 21, 1857–1862 (2007). References 52–55 describe the characterization of cell-free extracts, recapitulating many features of the miRNA-mediated repression established inmammalian and D. melanogaster cell lines.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wu, L., Fan, J. & Belasco, J. G. microRNAs direct rapid deadenylation of mRNA. Proc. Natl Acad. Sci. USA 103, 4034–4039 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chendrimada, T. P. et al. microRNA silencing through RISC recruitment of eIF6. Nature 447, 823–828 (2007). This report identifies eIF6 as a potential target of miRNA-meditated repression. The authors propose that, by interacting with eIF6, AGO proteins repress translation by preventing the 60S ribosomal subunit joining to the 40S initiation complex.

    Article  CAS  PubMed  Google Scholar 

  58. Russell, D. W. & Spremulli, L. L. Identification of a wheat germ ribosome dissociation factor distinct from initiation factor eIF-3. J. Biol. Chem. 253, 6647–6649 (1978).

    CAS  PubMed  Google Scholar 

  59. Sanvito, F. et al. The β4 integrin interactor p27(BBP/eIF6) is an essential nuclear matrix protein involved in 60S ribosomal subunit assembly. J. Cell Biol. 144, 823–837 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Si, K. & Maitra, U. The Saccharomyces cerevisiae homologue of mammalian translation initiation factor 6 does not function as a translation initiation factor. Mol. Cell Biol. 19, 1416–1426 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Basu, U., Si, K., Warner, J. R. & Maitra, U. The Saccharomyces cerevisiae TIF6 gene encoding translation initiation factor 6 is required for 60S ribosomal subunit biogenesis. Mol. Cell Biol. 21, 1453–1462 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sachs, A. B. & Davis, R. W. Translation initiation and ribosomal biogenesis: involvement of a putative rRNA helicase and RPL46. Science 247, 1077–1079 (1990).

    Article  CAS  PubMed  Google Scholar 

  63. Sachs, A. B. & Davis, R. W. The poly(A) binding protein is required for poly(A) shortening and 60S ribosomal subunit-dependent translation initiation. Cell 58, 857–867 (1989).

    Article  CAS  PubMed  Google Scholar 

  64. Olsen, P. H. & Ambros, V. The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev. Biol. 216, 671–680 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Seggerson, K., Tang, L. & Moss, E. G. Two genetic circuits repress the Caenorhabditis elegans heterochronic gene lin-28 after translation initiation. Dev. Biol. 243, 215–225 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Petersen, C. P., Bordeleau, M. E., Pelletier, J. & Sharp, P. A. Short RNAs repress translation after initiation in mammalian cells. Mol. Cell 21, 533–542 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Nottrott, S., Simard, M. J. & Richter, J. D. Human let-7a miRNA blocks protein production on actively translating polyribosomes. Nature Struct. Mol. Biol. 13, 1108–1114 (2006).

    Article  CAS  Google Scholar 

  68. Maroney, P. A., Yu, Y., Fisher, J. & Nilsen, T. W. Evidence that microRNAs are associated with translating messenger RNAs in human cells. Nature Struct. Mol. Biol. 13, 1102–1107 (2006). References 66 to 68 demonstrate that repressed mRNAs are associated with actively translating polyribosomes and argue that miRNAs block protein synthesis at steps after initiation. The data supporting this mechanism are also reported in references 64 and 65.

    Article  CAS  Google Scholar 

  69. Kim, J. et al. Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proc. Natl Acad. Sci. USA 101, 360–365 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Nelson, P. T., Hatzigeorgiou, A. G. & Mourelatos, Z. miRNP: mRNA association in polyribosomes in a human neuronal cell line. RNA 10, 387–394 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vasudevan, S. & Steitz, J. A. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell 128, 1105–1118 (2007). This paper demonstrates that interaction of AGO2 (in a complex with FXR1) with the mRNA 3′ UTR can, under specific cellular conditions, lead to upregulation rather than downregulation of translation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mootz, D., Ho, D. M. & Hunter, C. P. The STAR–Maxi-KH domain protein GLD-1 mediates a developmental switch in the translational control of C. elegans PAL-1. Development 131, 3263–3272 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Ruegsegger, U., Leber, J. H. & Walter, P. Block of HAC1 mRNA translation by long-range base pairing is released by cytoplasmic splicing upon induction of the unfolded protein response. Cell 107, 103–114 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Clark, I. E., Wyckoff, D. & Gavis, E. R. Synthesis of the posterior determinant nanos is spatially restricted by a novel cotranslational regulatory mechanism. Curr. Biol. 10, 1311–1314 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Braat, A. K., Yan, N., Arn, E., Harrison, D. & Macdonald, P. M. Localization-dependent oskar protein accumulation; control after the initiation of translation. Dev. Cell 7, 125–131 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Tomancak, P. et al. Global analysis of patterns of gene expression during Drosophila embryogenesis. Genome Biol. 8, R145 (2007).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  77. Bagga, S. et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122, 553–563 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Behm-Ansmant, I. et al. mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev. 20, 1885–1898 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Giraldez, A. J. et al. Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312, 75–79 (2006). This paper and references 56, 77 and 78 provide compelling evidence that miRNA can induce pronounced target mRNA degradation, which is initiated by removal of the poly(A) tail.

    Article  CAS  PubMed  Google Scholar 

  80. Wu, L. & Belasco, J. G. Micro-RNA regulation of the mammalian lin-28 gene during neuronal differentiation of embryonal carcinoma cells. Mol. Cell Biol. 25, 9198–9208 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rehwinkel, J. et al. Genome-wide analysis of mRNAs regulated by drosha and Argonaute proteins in Drosophila melanogaster. Mol. Cell Biol. 26, 2965–2975 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schmitter, D. et al. Effects of Dicer and Argonaute down-regulation on mRNA levels in human HEK293 cells. Nucleic Acids Res. 34, 4801–4815 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Eulalio, A. et al. Target-specific requirements for enhancers of decapping in miRNA-mediated gene silencing. Genes Dev. 21, 2558–2570 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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 

  85. Krutzfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).

    Article  PubMed  CAS  Google Scholar 

  86. Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell. Metab. 3, 87–98 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Linsley, P. S. et al. Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol. Cell Biol. 27, 2240–2252 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Parker, R. & Song, H. The enzymes and control of eukaryotic mRNA turnover. Nature Struct. Mol. Biol. 11, 121–127 (2004).

    Article  CAS  Google Scholar 

  89. Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell 25, 635–646 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Ding, L., Spencer, A., Morita, K. & Han, M. The developmental timing regulator AIN-1 interacts with miRISCs and may target the argonaute protein ALG-1 to cytoplasmic P bodies in C. elegans. Mol. Cell 19, 437–447 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Liu, J. et al. A role for the P-body component GW182 in microRNA function. Nature Cell Biol. 7, 1261–1266 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Jakymiw, A. et al. Disruption of GW bodies impairs mammalian RNA interference. Nature Cell Biol. 7, 1267–1274 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Meister, G. et al. Identification of novel argonaute-associated proteins. Curr. Biol. 15, 2149–2155 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Till, S. et al. A conserved motif in Argonaute-interacting proteins mediates functional interactions through the Argonaute PIWI domain. Nature Struct. Mol. Biol. 14, 897–903 (2007).

    Article  CAS  Google Scholar 

  95. Mishima, Y. et al. Differential regulation of germline mRNAs in soma and germ cells by zebrafish miR-430. Curr. Biol. 16, 2135–2142 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Aleman, L. M., Doench, J. & Sharp, P. A. Comparison of siRNA-induced off-target RNA and protein effects. RNA 13, 385–395 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Anderson, P. & Kedersha, N. RNA granules. J. Cell Biol. 172, 803–808 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Brengues, M., Teixeira, D. & Parker, R. Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies. Science 310, 486–489 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Brengues, M. & Parker, R. Accumulation of polyadenylated mRNA, Pab1p, eIF4E, and eIF4G with P-bodies in Saccharomyces cerevisiae. Mol. Biol. Cell 18, 2592–2602 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Liu, J., Valencia-Sanchez, M. A., Hannon, G. J. & Parker, R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nature Cell Biol. 7, 719–723 (2005). This paper and references 43, 45, 78, 91 and 92 establish the connection between miRNA-mediated repression and P-bodies by demonstrating that miRNP components and repressed mRNAs accumulate in P-bodies and that many P-body proteins are essential for the repression.

    Article  CAS  PubMed  Google Scholar 

  101. Leung, A. K., Calabrese, J. M. & Sharp, P. A. Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules. Proc. Natl Acad. Sci. USA 103, 18125–18130 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Huang, J. et al. Derepression of micro-RNA-mediated protein translation inhibition by apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) and its family members. J. Biol. Chem. 282, 33632–33640 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Eulalio, A., Behm-Ansmant, I., Schweizer, D. & Izaurralde, E. P-body formation is a consequence, not the cause, of RNA-mediated gene silencing. Mol. Cell Biol. 27, 3970–3981 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Chu, C. Y. & Rana, T. M. Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biol. 4, 1122–1136 (2006). This paper and reference 83 identify the decapping activators that are associated with P-bodies as proteins that are essential for miRNA-mediated repression.

    Article  CAS  Google Scholar 

  105. Decker, C. J., Teixeira, D. & Parker, R. Edc3p and a glutamine/asparagine-rich domain of Lsm4p function in processing body assembly in Saccharomyces cerevisiae. J. Cell Biol. 179, 437–449 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Rehwinkel, J., Behm-Ansmant, I., Gatfield, D. & Izaurralde, E. A crucial role for GW182 and the DCP1:DCP2 decapping complex in miRNA-mediated gene silencing. RNA 11, 1640–1647 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Barbee, S. A. et al. Staufen- and FMRP-containing neuronal RNPs are structurally and functionally related to somatic P bodies. Neuron 52, 997–1009 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Pauley, K. M. et al. Formation of GW bodies is a consequence of microRNA genesis. EMBO Rep. 7, 904–910 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Coller, J. & Parker, R. General translational repression by activators of mRNA decapping. Cell 122, 875–886 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Minshall, N. & Standart, N. The active form of Xp54 RNA helicase in translational repression is an RNA-mediated oligomer. Nucleic Acids Res. 32, 1325–1334 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Smillie, D. A. & Sommerville, J. RNA helicase p54 (DDX6) is a shuttling protein involved in nuclear assembly of stored mRNP particles. J. Cell Sci. 115, 395–407 (2002).

    CAS  PubMed  Google Scholar 

  112. Ferraiuolo, M. A. et al. A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay. J. Cell Biol. 170, 913–924 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Andrei, M. A. et al. A role for eIF4E and eIF4E-transporter in targeting mRNPs to mammalian processing bodies. RNA 11, 717–727 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tanaka, K. J. et al. RAP55, a cytoplasmic mRNP component, represses translation in Xenopus oocytes. J. Biol. Chem. 281, 40096–40106 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Kedersha, N. et al. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J. Cell Biol. 169, 871–884 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Durand, S. et al. Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies. J. Cell Biol. 178, 1145–1160 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tahbaz, N., Carmichael, J. B. & Hobman, T. C. GERp95 belongs to a family of signal-transducing proteins and requires Hsp90 activity for stability and Golgi localization. J. Biol. Chem. 276, 43294–43299 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Tahbaz, N. et al. Characterization of the interactions between mammalian PAZ PIWI domain proteins and Dicer. EMBO Rep. 5, 189–194 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Mazroui, R. et al. Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor 2α phosphorylation. Mol. Biol. Cell 17, 4212–4219 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schratt, G. M. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289 (2006). This paper and reference 45 provide the first evidence that, under specific cellular conditions, mRNAs can be relieved from the miRNA-mediated repression and relocate from P-bodies to enter active translation.

    Article  CAS  PubMed  Google Scholar 

  121. Ashraf, S. I., McLoon, A. L., Sclarsic, S. M. & Kunes, S. Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila. Cell 124, 191–205 (2006).

    CAS  PubMed  Google Scholar 

  122. Sutton, M. A. & Schuman, E. M. Dendritic protein synthesis, synaptic plasticity, and memory. Cell 127, 49–58 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Kosik, K. S. The neuronal microRNA system. Nature Rev. Neurosci. 7, 911–920 (2006).

    Article  CAS  Google Scholar 

  124. Lu, J. Y. & Schneider, R. J. Tissue distribution of AU-rich mRNA-binding proteins involved in regulation of mRNA decay. J. Biol. Chem. 279, 12974–12979 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Ruby, J. G., Jan, C. H. & Bartel, D. P. Intronic microRNA precursors that bypass drosha processing. Nature 448, 83–86 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Okamura, K., Hagen, J. W., Duan, H., Tyler, D. M. & Lai, E. C. The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130, 89–100 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Berezikov, E., Chung, W. J., Willis, J., Cuppen, E. & Lai, E. C. Mammalian mirtron genes. Mol. Cell 28, 328–336 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Jin, P., Alisch, R. S. & Warren, S. T. RNA and microRNAs in fragile X mental retardation. Nature Cell Biol. 6, 1048–1053 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Gaidatzis, D., van Nimwegen, E., Hausser, J. & Zavolan, M. Inference of miRNA targets using evolutionary conservation and pathway analysis. BMC Bioinformatics 8, 69 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Kertesz, M., Iovino, N., Unnerstall, U., Gaul, U. & Segal, E. The role of site accessibility in microRNA target recognition. Nature Genet. 39, 1278–1284 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Vella, M. C., Choi, E. Y., Lin, S. Y., Reinert, K. & Slack, F. J. The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3′ UTR. Genes Dev. 18, 132–137 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).

    Article  CAS  PubMed  Google Scholar 

  133. Raught, B. & Gingras, A.-C. in Translational Control in Biology and Medicine (eds Mathews, M. B., Sonenberg, N. & Hershey, J. B.) 369–400 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2007).

    Google Scholar 

  134. Herbert, T. P. & Proud, C. G. in Translational Control in Biology and Medicine (eds Mathews, M. B., Sonenberg, N. & Hershey, J. B.) 601–624 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2007).

    Google Scholar 

  135. Wilczynska, A., Aigueperse, C., Kress, M., Dautry, F. & Weil, D. The translational regulator CPEB1 provides a link between dcp1 bodies and stress granules. J. Cell Sci. 118, 981–992 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Schneider, M. D. et al. gawky is a component of cytoplasmic mRNA processing bodies required for early Drosophila development. J. Cell Biol. 174, 349–358 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Vasudevan S, Tong Y, Steitz J. A. Switching from repression to activation: microRNAs can up-regulate translation. Science 318, 1931–1934 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Kedde, M. et al. RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131, 1273–1286 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Jackson for drawing our attention to the bypass suppressors of the yeast Pab1 deletion. We thank H. Grosshans, N. Standart, R. Jackson and members of the Filipowicz and Sonenberg groups for their comments. S.N.B is a recipient of Human Frontier Science Program Organization (HFSPO) long-term fellowship. The Friedrich Miescher Institute is supported by the Novartis Research Foundation. N.S. was supported by grants from the HFSPO and the Canadian Institute of Health Research and is a Howard Hughes Medical Institute International Scholar. Research by W.F. is also supported by the EC FP6 Program 'Sirocco'.

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Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Basel, 4002, Switzerland

    Witold Filipowicz & Suvendra N. Bhattacharyya

  2. Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, H3G 1Y6, Quebec, Canada

    Nahum Sonenberg

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  1. Witold Filipowicz
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  2. Suvendra N. Bhattacharyya
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  3. Nahum Sonenberg
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Correspondence to Witold Filipowicz or Nahum Sonenberg.

Supplementary information

Supplementary information S1 (table)

Examples of miRNA-targeted mRNAs, repression of which is associated with no or only minimal mRNA degradation. (PDF 228 kb)

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Glossary

Dicer

An RNase III family endonuclease that processes dsRNA and pre-miRNAs into small interfering RNAs and microRNAs, respectively.

Small interfering RNAs

(siRNAs). Small RNAs that are similar in size to microRNAs but are derived from the progressive cleavage of long dsRNA by Dicer. Upon incorporation into an RISC, siRNAs guide the endonucleolytic cleavage of the target mRNA.

RNA interference

The dsRNA-induced, sequence-homology dependent gene-silencing mechanism. The dsRNA is processed to siRNAs, which, upon incorporation into an RISC, guide the endonucleolytic cleavage of the target mRNA.

RNA-induced silencing complex

(RISC). The ribonucleoprotein complex, consisting of small interfering RNA and an AGO protein, that harbours the 'slicer' activity, which cleaves an mRNA target in the middle of siRNA–mRNA complementarity.

micro-ribonucleoprotein

(miRNP). A ribonucleoprotein complex containing a miRNA and one of the AGO proteins. Depending on the identity of the associated AGO, it might harbour a 'slicer' activity, characteristic of an RISC.

m7G cap

The 7-methylguanosine (m7G) that is linked by a 5–5′ triphosphate bridge to the first transcribed nucleoside at the 5′ end of eukaryotic mRNAs.

Internal ribosomal entry site

(IRES). An RNA element, usually present in the 5′ UTR, that allows m7G-cap-independent association of ribosome with mRNA.

ApppN cap

An unmethylated cap analogue that is not bound by eIF4E. The mRNAs with an artificially introduced ApppN cap instead of a physiological m7GpppN cap are translated inefficiently.

Polysome gradient analysis

A technique that involves the sedimentation of cell extracts through a gradient of sucrose or glycerol, thereby allowing the determination of the number of ribosomes that are associated with a specific mRNA. Repression of translational initiation, which results in the less efficient loading of ribosomes onto mRNA, is usually associated with a shift of mRNA towards the top of the gradient.

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Filipowicz, W., Bhattacharyya, S. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?. Nat Rev Genet 9, 102–114 (2008). https://doi.org/10.1038/nrg2290

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