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MicroRNA assassins: factors that regulate the disappearance of miRNAs

Abstract

MicroRNAs (miRNAs) control essential gene regulatory pathways in plants and animals. Serving as guides in silencing complexes, miRNAs direct Argonaute proteins to specific target messenger RNAs to repress protein expression. The mature, 22-nucleotide (nt) miRNA is the product of multiple processing steps, and recent studies have uncovered factors that directly control the stability of the functional RNA form. Although alteration of miRNA levels has been linked to numerous disease states, the mechanisms responsible for stabilized or reduced miRNA expression have been largely elusive. The discovery of specific cis-acting modifications and trans-acting proteins that affect miRNA half-life reveals new elements that contribute to the homeostasis of these vital regulatory molecules.

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Figure 1: A general model of miRNA biogenesis and function6,7,8,9.
Figure 2: Proteins that regulate miRNA stability.
Figure 3: Outstanding questions regarding factors that regulate miRNA stability.

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References

  1. Griffiths-Jones, S., Saini, H.K., van Dongen, S. & Enright, A.J. miRBase: tools for microRNA genomics. Nucleic Acids Res. 36, D154–D158 (2008).

    Article  CAS  Google Scholar 

  2. Hebert, S.S. & De Strooper, B. Alterations of the microRNA network cause neurodegenerative disease. Trends Neurosci. 32, 199–206 (2009).

    Article  CAS  Google Scholar 

  3. Latronico, M.V. & Condorelli, G. MicroRNAs and cardiac pathology. Nat. Rev. Cardiol. 6, 419–429 (2009).

    Article  Google Scholar 

  4. Negrini, M., Nicoloso, M.S. & Calin, G.A. MicroRNAs and cancer—new paradigms in molecular oncology. Curr. Opin. Cell Biol. 21, 470–479 (2009).

    Article  CAS  Google Scholar 

  5. Chuck, G., Candela, H. & Hake, S. Big impacts by small RNAs in plant development. Curr. Opin. Plant Biol. 12, 81–86 (2009).

    Article  CAS  Google Scholar 

  6. Chen, X. Small RNAs and their roles in plant development. Annu. Rev. Cell Dev. Biol. 25, 21–44 (2009).

    Article  Google Scholar 

  7. Davis, B.N. & Hata, A. Regulation of microRNA biogenesis: A miRiad of mechanisms. Cell Commun. Signal. 7, 18 (2009).

    Article  Google Scholar 

  8. Winter, J., Jung, S., Keller, S., Gregory, R.I. & Diederichs, S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat. Cell Biol. 11, 228–234 (2009).

    Article  CAS  Google Scholar 

  9. Chekulaeva, M. & Filipowicz, W. Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. Curr. Opin. Cell Biol. 21, 452–460 (2009).

    Article  CAS  Google Scholar 

  10. Thomson, J.M. et al. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 20, 2202–2207 (2006).

    Article  CAS  Google Scholar 

  11. Khvorova, A., Reynolds, A. & Jayasena, S.D. Functional siRNAs and miRNAs exhibit strand bias. Cell 115, 209–216 (2003).

    Article  CAS  Google Scholar 

  12. Schwarz, D.S. et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell 115, 199–208 (2003).

    Article  CAS  Google Scholar 

  13. Diederichs, S. & Haber, D.A. Dual role for argonautes in microRNA processing and posttranscriptional regulation of microRNA expression. Cell 131, 1097–1108 (2007).

    Article  CAS  Google Scholar 

  14. 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 

  15. O'Carroll, D. et al. A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway. Genes Dev. 21, 1999–2004 (2007).

    Article  CAS  Google Scholar 

  16. Vaucheret, H., Vazquez, F., Crete, P. & Bartel, D.P. The action of ARGONAUTE1 in the miRNA pathway and its regulation by the miRNA pathway are crucial for plant development. Genes Dev. 18, 1187–1197 (2004).

    Article  CAS  Google Scholar 

  17. Yu, B. et al. Methylation as a crucial step in plant microRNA biogenesis. Science 307, 932–935 (2005).

    Article  CAS  Google Scholar 

  18. Li, J., Yang, Z., Yu, B., Liu, J. & Chen, X. Methylation protects miRNAs and siRNAs from a 3′-end uridylation activity in Arabidopsis. Curr. Biol. 15, 1501–1507 (2005).

    Article  CAS  Google Scholar 

  19. Ramachandran, V. & Chen, X. Degradation of microRNAs by a family of exoribonucleases in Arabidopsis. Science 321, 1490–1492 (2008).

    Article  CAS  Google Scholar 

  20. Horwich, M.D. et al. The Drosophila RNA methyltransferase, DmHen1, modifies germline piRNAs and single-stranded siRNAs in RISC. Curr. Biol. 17, 1265–1272 (2007).

    Article  CAS  Google Scholar 

  21. Kirino, Y. & Mourelatos, Z. The mouse homolog of HEN1 is a potential methylase for Piwi-interacting RNAs. RNA 13, 1397–1401 (2007).

    Article  CAS  Google Scholar 

  22. Saito, K. et al. Pimet, the Drosophila homolog of HEN1, mediates 2′-O-methylation of Piwi-interacting RNAs at their 3′ ends. Genes Dev. 21, 1603–1608 (2007).

    Article  CAS  Google Scholar 

  23. Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).

    Article  CAS  Google Scholar 

  24. Morin, R.D. et al. Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells. Genome Res. 18, 610–621 (2008).

    Article  CAS  Google Scholar 

  25. Reid, J.G. et al. Mouse let-7 miRNA populations exhibit RNA editing that is constrained in the 5′-seed/cleavage/anchor regions and stabilize predicted mmu-let-7a–mRNA duplexes. Genome Res. 18, 1571–1581 (2008).

    Article  CAS  Google Scholar 

  26. Ruby, J.G. et al. Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell 127, 1193–1207 (2006).

    Article  CAS  Google Scholar 

  27. Ebhardt, H.A. et al. Meta-analysis of small RNA-sequencing errors reveals ubiquitous post-transcriptional RNA modifications. Nucleic Acids Res. 37, 2461–2470 (2009).

    Article  CAS  Google Scholar 

  28. Azuma-Mukai, A. et al. Characterization of endogenous human Argonautes and their miRNA partners in RNA silencing. Proc. Natl. Acad. Sci. USA 105, 7964–7969 (2008).

    Article  CAS  Google Scholar 

  29. Katoh, T. et al. Selective stabilization of mammalian microRNAs by 3′ adenylation mediated by the cytoplasmic poly(A) polymerase GLD-2. Genes Dev. 23, 433–438 (2009).

    Article  CAS  Google Scholar 

  30. Lu, S., Sun, Y.H. & Chiang, V.L. Adenylation of plant miRNAs. Nucleic Acids Res. 37, 1878–1885 (2009).

    Article  CAS  Google Scholar 

  31. Chatterjee, S. & Grosshans, H. Active turnover modulates mature microRNA activity in Caenorhabditis elegans. Nature 461, 546–549 (2009).

    Article  CAS  Google Scholar 

  32. Gy, I. et al. Arabidopsis FIERY1, XRN2, and XRN3 are endogenous RNA silencing suppressors. Plant Cell 19, 3451–3461 (2007).

    Article  CAS  Google Scholar 

  33. Ballarino, M. et al. Coupled RNA processing and transcription of intergenic primary microRNAs. Mol. Cell. Biol. 29, 5632–5638 (2009).

    Article  CAS  Google Scholar 

  34. Morlando, M. et al. Primary microRNA transcripts are processed co-transcriptionally. Nat. Struct. Mol. Biol. 15, 902–909 (2008).

    Article  CAS  Google Scholar 

  35. Buratowski, S. Connections between mRNA 3′ end processing and transcription termination. Curr. Opin. Cell Biol. 17, 257–261 (2005).

    Article  CAS  Google Scholar 

  36. Doma, M.K. & Parker, R. RNA quality control in eukaryotes. Cell 131, 660–668 (2007).

    Article  CAS  Google Scholar 

  37. Weinmann, L. et al. Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell 136, 496–507 (2009).

    Article  CAS  Google Scholar 

  38. Gatfield, D. et al. Integration of microRNA miR-122 in hepatic circadian gene expression. Genes Dev. 23, 1313–1326 (2009).

    Article  CAS  Google Scholar 

  39. Lee, Y. et al. The role of PACT in the RNA silencing pathway. EMBO J. 25, 522–532 (2006).

    Article  CAS  Google Scholar 

  40. van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).

    Article  CAS  Google Scholar 

  41. van Wolfswinkel, J.C. et al. CDE-1 affects chromosome segregation through uridylation of CSR-1-bound siRNAs. Cell 139, 135–148 (2009).

    Article  CAS  Google Scholar 

  42. Hagan, J.P., Piskounova, E. & Gregory, R.I. Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat. Struct. Mol. Biol. 16, 1021–1025 (2009).

    Article  CAS  Google Scholar 

  43. Heo, I. et al. Lin28 mediates the terminal uridylation of let-7 precursor microRNA. Mol. Cell 32, 276–284 (2008).

    Article  CAS  Google Scholar 

  44. Heo, I. et al. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation. Cell 138, 696–708 (2009).

    Article  CAS  Google Scholar 

  45. Lehrbach, N.J. et al. LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 microRNA processing in Caenorhabditis elegans. Nat. Struct. Mol. Biol. 16, 1016–1020 (2009).

    Article  CAS  Google Scholar 

  46. Jones, M.R. et al. Zcchc11-dependent uridylation of microRNA directs cytokine expression. Nat. Cell Biol. 11, 1157–1163 (2009).

    Article  CAS  Google Scholar 

  47. Martin, G. & Keller, W. RNA-specific ribonucleotidyl transferases. RNA 13, 1834–1849 (2007).

    Article  CAS  Google Scholar 

  48. Chen, Y., Sinha, K., Perumal, K. & Reddy, R. Effect of 3′ terminal adenylic acid residue on the uridylation of human small RNAs in vitro and in frog oocytes. RNA 6, 1277–1288 (2000).

    Article  CAS  Google Scholar 

  49. Chi, S.W., Zang, J.B., Mele, A. & Darnell, R.B. Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460, 479–486 (2009).

    Article  CAS  Google Scholar 

  50. Khan, A.A. et al. Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs. Nat. Biotechnol. 27, 549–555 (2009).

    Article  CAS  Google Scholar 

  51. Sood, P., Krek, A., Zavolan, M., Macino, G. & Rajewsky, N. Cell-type–specific signatures of microRNAs on target mRNA expression. Proc. Natl. Acad. Sci. USA 103, 2746–2751 (2006).

    Article  CAS  Google Scholar 

  52. Rajasethupathy, P. et al. Characterization of small RNAs in aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron 63, 803–817 (2009).

    Article  CAS  Google Scholar 

  53. Sethi, P. & Lukiw, W.J. Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer's disease temporal lobe neocortex. Neurosci. Lett. 459, 100–104 (2009).

    Article  CAS  Google Scholar 

  54. Ciaudo, C. et al. Highly dynamic and sex-specific expression of microRNAs during early ES cell differentiation. PLoS Genet. 5, e1000620 (2009).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank D. Zisoulis for critical reading of the manuscript and our colleagues for helpful discussions. Z.S.K. is supported in part by a US National Institutes of Health Cellular and Molecular Graduate Student Training Grant, and research in the Pasquinelli laboratory is supported by grants from the US National Institutes of Health (GM071654-01) and the Keck, Searle, V, Emerald and Peter Gruber Foundations.

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Correspondence to Amy E Pasquinelli.

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Kai, Z., Pasquinelli, A. MicroRNA assassins: factors that regulate the disappearance of miRNAs. Nat Struct Mol Biol 17, 5–10 (2010). https://doi.org/10.1038/nsmb.1762

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