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:

Swiss army knives: non-canonical functions of nuclear Drosha and Dicer

Nature Reviews Molecular Cell Biology volume 16, pages 417–430 (2015)Cite this article

Subjects

Key Points

  • Transcriptional gene silencing (TGS), post-transcriptional gene silencing (PTGS), RNA-directed DNA methylation (RdDM) and RNA activation (RNAa) are types of nuclear RNAi.

  • Nuclear RNAi regulates genome editing and shapes the response to environmental stimuli.

  • Nuclear RNAi factors promote the DNA damage response.

  • Non-canonical functions of Drosha and Dicer include transcription regulation and RNA metabolism.

  • Specialized, truncated Dicer isoforms were identified in mice and Caenorhabditis elegans that regulate the production of endogenous siRNAs (endo-siRNAs) and the detoxification of double-stranded RNA from cells.

Abstract

The RNase III enzymes Drosha and Dicer are essential for the production of small non-coding RNAs (ncRNAs). In canonical RNAi, microRNAs (miRNAs) regulate gene expression by post-transcriptional gene silencing. In non-canonical RNAi, nuclear RNAi factors generate small ncRNAs that are essential for transcriptional gene silencing. Recent evidence points to the existence of additional non-canonical nuclear RNAi functions in various organisms, including in genome maintenance and editing, as well as in DNA repair. Drosha and Dicer directly regulate gene expression and RNA metabolism at different stages, such as transcriptional initiation and termination, and the processing of various RNA species, including pre-mRNAs. Furthermore, Dicer isoforms were recently discovered and attributed with roles in apoptosis, development and disease.

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 different types of nuclear RNAi.
Figure 2: Roles of nuclear RNAi factors in transcription initiation and termination.
Figure 3: The roles of RNAi factors in the regulation of splicing in mammals.
Figure 4: RNAi factor involvement in transposon silencing and RNA detoxification.
Figure 5: Specialized Dicer isoforms in mouse oocytes and Caenorhabditis elegans somatic cells.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Ratcliff, F., Harrison, B. D. & Baulcombe, D. C. A similarity between viral defense and gene silencing in plants. Science 276, 1558–1560 (1997).

    CAS  PubMed  Google Scholar 

  3. Im, H. I. & Kenny, P. J. MicroRNAs in neuronal function and dysfunction. Trends Neurosci. 35, 325–334 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lujambio, A. & Lowe, S. W. The microcosmos of cancer. Nature 482, 347–355 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Mendell, J. T. & Olson, E. N. MicroRNAs in stress signaling and human disease. Cell 148, 1172–1187 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Du, N. H., Arpat, A. B., De Matos, M. & Gatfield, D. MicroRNAs shape circadian hepatic gene expression on a transcriptome-wide scale. eLife 3, e02510 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Friedman, R. C., Farh, K. K., Burge, C. B. & Bartel, D. P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Court, D. L. et al. RNase III: genetics and function; structure and mechanism. Annu. Rev. Genet. 47, 405–431 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Drinnenberg, I. A. et al. RNAi in budding yeast. Science 326, 544–550 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kawamata, T. & Tomari, Y. Making RISC. Trends Biochem. Sci. 35, 368–376 (2010).

    CAS  PubMed  Google Scholar 

  11. Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).

    CAS  PubMed  Google Scholar 

  12. Meister, G. Argonaute proteins: functional insights and emerging roles. Nat. Rev. Genet. 14, 447–459 (2013).

    CAS  PubMed  Google Scholar 

  13. Siomi, M. C., Sato, K., Pezic, D. & Aravin, A. A. PIWI-interacting small RNAs: the vanguard of genome defence. Nat. Rev. Mol. Cell Biol. 12, 246–258 (2011).

    CAS  PubMed  Google Scholar 

  14. Baulcombe, D. RNA silencing in plants. Nature 431, 356–363 (2004).

    CAS  PubMed  Google Scholar 

  15. Gullerova, M. & Proudfoot, N. J. Cohesin complex promotes transcriptional termination between convergent genes in S. pombe. Cell 132, 983–995 (2008).

    CAS  PubMed  Google Scholar 

  16. Kato, H. et al. RNA polymerase II is required for RNAi-dependent heterochromatin assembly. Science 309, 467–469 (2005).

    CAS  PubMed  Google Scholar 

  17. Moazed, D. Molecular biology. Rejoice—RNAi for yeast. Science 326, 533–534 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Proudfoot, N. & Gullerova, M. Gene silencing CUTs both ways. Cell 131, 649–651 (2007).

    CAS  PubMed  Google Scholar 

  19. Okamura, K. & Lai, E. C. Endogenous small interfering RNAs in animals. Nat. Rev. Mol. Cell Biol. 9, 673–678 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Weick, E. M. & Miska, E. A. piRNAs: from biogenesis to function. Development 141, 3458–3471 (2014).

    CAS  PubMed  Google Scholar 

  21. Chong, M. M. et al. Canonical and alternate functions of the microRNA biogenesis machinery. Genes Dev. 24, 1951–1960 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kaneko, H. et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471, 325–330 (2011). This study shows a miRNA-independent function for Dicer in retrotransposon transcript degradation.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Knuckles, P. et al. Drosha regulates neurogenesis by controlling neurogenin 2 expression independent of microRNAs. Nat. Neurosci. 15, 962–969 (2012).

    CAS  PubMed  Google Scholar 

  24. Tarallo, V. et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149, 847–859 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cifuentes, D. et al. A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 328, 1694–1698 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zamudio, J. R., Kelly, T. J. & Sharp, P. A. Argonaute-bound small RNAs from promoter-proximal RNA polymerase II. Cell 156, 920–934 (2014). This study describes an AGO-dependent class of non-canonical miRNAs derived from promoter regions.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Weiberg, A. et al. Fungal small RNAs suppress plant immunity by hijacking host RNA interference pathways. Science 342, 118–123 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Buhler, M., Verdel, A. & Moazed, D. Tethering RITS to a nascent transcript initiates RNAi- and heterochromatin-dependent gene silencing. Cell 125, 873–886 (2006).

    CAS  PubMed  Google Scholar 

  31. Camblong, J., Iglesias, N., Fickentscher, C., Dieppois, G. & Stutz, F. Antisense RNA stabilization induces transcriptional gene silencing via histone deacetylation in S. cerevisiae. Cell 131, 706–717 (2007).

    CAS  PubMed  Google Scholar 

  32. Colmenares, S. U., Buker, S. M., Buhler, M., Dlakic, M. & Moazed, D. Coupling of double-stranded RNA synthesis and siRNA generation in fission yeast RNAi. Mol. Cell 27, 449–461 (2007).

    CAS  PubMed  Google Scholar 

  33. Zhang, K., Mosch, K., Fischle, W. & Grewal, S. I. Roles of the Clr4 methyltransferase complex in nucleation, spreading and maintenance of heterochromatin. Nat. Struct. Mol. Biol. 15, 381–388 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  35. Yu, R., Jih, G., Iglesias, N. & Moazed, D. Determinants of heterochromatic siRNA biogenesis and function. Mol. Cell 53, 262–276 (2014).

    CAS  PubMed  Google Scholar 

  36. Zaratiegui, M. et al. RNAi promotes heterochromatic silencing through replication-coupled release of RNA Pol II. Nature 479, 135–138 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Castel, S. E. & Martienssen, R. A. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat. Rev. Genet. 14, 100–112 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Gao, Z. et al. An RNA polymerase II- and AGO4-associated protein acts in RNA-directed DNA methylation. Nature 465, 106–109 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wassenegger, M., Heimes, S., Riedel, L. & Sanger, H. L. RNA-directed de novo methylation of genomic sequences in plants. Cell 76, 567–576 (1994).

    CAS  PubMed  Google Scholar 

  40. Onodera, Y. et al. Plant nuclear RNA polymerase IV mediates siRNA and DNA methylation-dependent heterochromatin formation. Cell 120, 613–622 (2005).

    CAS  PubMed  Google Scholar 

  41. Ye, R. et al. Cytoplasmic assembly and selective nuclear import of Arabidopsis Argonaute4/siRNA complexes. Mol. Cell 46, 859–870 (2012).

    CAS  PubMed  Google Scholar 

  42. Wierzbicki, A. T., Haag, J. R. & Pikaard, C. S. Noncoding transcription by RNA polymerase Pol IVb/Pol V mediates transcriptional silencing of overlapping and adjacent genes. Cell 135, 635–648 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wierzbicki, A. T., Ream, T. S., Haag, J. R. & Pikaard, C. S. RNA polymerase V transcription guides ARGONAUTE4 to chromatin. Nat. Genet. 41, 630–634 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Place, R. F., Li, L. C., Pookot, D., Noonan, E. J. & Dahiya, R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc. Natl Acad. Sci. USA 105, 1608–1613 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang, V. et al. Upregulation of cyclin B1 by miRNA and its implications in cancer. Nucleic Acids Res. 40, 1695–1707 (2012).

    CAS  PubMed  Google Scholar 

  46. Kim, D. H., Saetrom, P., Snove, O. Jr & Rossi, J. J. MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc. Natl Acad. Sci. USA 105, 16230–16235 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Younger, S. T. & Corey, D. R. Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters. Nucleic Acids Res. 39, 5682–5691 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Keller, C., Kulasegaran-Shylini, R., Shimada, Y., Hotz, H. R. & Buhler, M. Noncoding RNAs prevent spreading of a repressive histone mark. Nat. Struct. Mol. Biol. 20, 994–1000 (2013).

    CAS  PubMed  Google Scholar 

  49. Marina, D. B., Shankar, S., Natarajan, P., Finn, K. J. & Madhani, H. D. A conserved ncRNA-binding protein recruits silencing factors to heterochromatin through an RNAi-independent mechanism. Genes Dev. 27, 1851–1856 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Bohmdorfer, G. et al. RNA-directed DNA methylation requires stepwise binding of silencing factors to long non-coding RNA. Plant J. 79, 181–191 (2014).

    PubMed  PubMed Central  Google Scholar 

  51. Dang, Y., Li, L., Guo, W., Xue, Z. & Liu, Y. Convergent transcription induces dynamic DNA methylation at disiRNA loci. PLoS Genet. 9, e1003761 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Guang, S. et al. Small regulatory RNAs inhibit RNA polymerase II during the elongation phase of transcription. Nature 465, 1097–1101 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Guang, S. et al. An Argonaute transports siRNAs from the cytoplasm to the nucleus. Science 321, 537–541 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103 (2007).

    CAS  PubMed  Google Scholar 

  55. Gagnon, K. T., Li, L., Chu, Y., Janowski, B. A. & Corey, D. R. RNAi factors are present and active in human cell nuclei. Cell Rep. 6, 211–221 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Chowdhury, D., Choi, Y. E. & Brault, M. E. Charity begins at home: non-coding RNA functions in DNA repair. Nat. Rev. Mol. Cell Biol. 14, 181–189 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Lee, H. C. et al. qiRNA is a new type of small interfering RNA induced by DNA damage. Nature 459, 274–277 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Francia, S. et al. Site-specific DICER and DROSHA RNA products control the DNA-damage response. Nature 488, 231–235 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Wei, W. et al. A role for small RNAs in DNA double-strand break repair. Cell 149, 101–112 (2012). This study shows that DNA DSB-derived small RNAs have a role in DSB repair.

    CAS  PubMed  Google Scholar 

  60. Peng, J. C. & Karpen, G. H. H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nat. Cell Biol. 9, 25–35 (2007).

    CAS  PubMed  Google Scholar 

  61. Peng, J. C. & Karpen, G. H. Heterochromatic genome stability requires regulators of histone H3 K9 methylation. PLoS Genet. 5, e1000435 (2009).

    PubMed  PubMed Central  Google Scholar 

  62. Michalik, K. M., Bottcher, R. & Forstemann, K. A small RNA response at DNA ends in Drosophila. Nucleic Acids Res. 40, 9596–9603 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Vannini, A. & Cramer, P. Conservation between the RNA polymerase I, II, and III transcription initiation machineries. Mol. Cell 45, 439–446 (2012).

    CAS  PubMed  Google Scholar 

  64. Gromak, N. et al. Drosha regulates gene expression independently of RNA cleavage function. Cell Rep. 5, 1499–1510 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Woolcock, K. J., Gaidatzis, D., Punga, T. & Buhler, M. Dicer associates with chromatin to repress genome activity in Schizosaccharomyces pombe. Nat. Struct. Mol. Biol. 18, 94–99 (2011).

    CAS  PubMed  Google Scholar 

  66. Woolcock, K. J. et al. RNAi keeps Atf1-bound stress response genes in check at nuclear pores. Genes Dev. 26, 683–692 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Emmerth, S. et al. Nuclear retention of fission yeast dicer is a prerequisite for RNAi-mediated heterochromatin assembly. Dev. Cell 18, 102–113 (2010).

    CAS  PubMed  Google Scholar 

  68. Barraud, P. et al. An extended dsRBD with a novel zinc-binding motif mediates nuclear retention of fission yeast Dicer. EMBO J. 30, 4223–4235 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Shapiro, J. S., Langlois, R. A., Pham, A. M. & Tenoever, B. R. Evidence for a cytoplasmic microprocessor of pri-miRNAs. RNA 18, 1338–1346 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Shapiro, J. S. et al. Drosha as an interferon-independent antiviral factor. Proc. Natl Acad. Sci. USA 111, 7108–7113 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Burton, N. O., Burkhart, K. B. & Kennedy, S. Nuclear RNAi maintains heritable gene silencing in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 108, 19683–19688 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Gu, S. G. et al. Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3 lysine 9 methylation footprint. Nat. Genet. 44, 157–164 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Cecere, G., Hoersch, S., O' Keeffe, S., Sachidanandam, R. & Grishok, A. Global effects of the CSR-1 RNA interference pathway on the transcriptional landscape. Nat. Struct. Mol. Biol. 21, 358–365 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Cernilogar, F. M. et al. Chromatin-associated RNA interference components contribute to transcriptional regulation in Drosophila. Nature 480, 391–395 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Chendrimada, T. P. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436, 740–744 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Redfern, A. D. et al. RNA-induced silencing complex (RISC) proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators. Proc. Natl Acad. Sci. USA 110, 6536–6541 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Lanz, R. B. et al. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 97, 17–27 (1999).

    CAS  PubMed  Google Scholar 

  79. Mapendano, C. K., Lykke-Andersen, S., Kjems, J., Bertrand, E. & Jensen, T. H. Crosstalk between mRNA 3′ end processing and transcription initiation. Mol. Cell 40, 410–422 (2010).

    CAS  PubMed  Google Scholar 

  80. West, S. & Proudfoot, N. J. Transcriptional termination enhances protein expression in human cells. Mol. Cell 33, 354–364 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Di Giammartino, D. C., Nishida, K. & Manley, J. L. Mechanisms and consequences of alternative polyadenylation. Mol. Cell 43, 853–866 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Proudfoot, N. J. Ending the message: poly(A) signals then and now. Genes Dev. 25, 1770–1782 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Iseli, C. et al. Long-range heterogeneity at the 3′ ends of human mRNAs. Genome Res. 12, 1068–1074 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kuehner, J. N., Pearson, E. L. & Moore, C. Unravelling the means to an end: RNA polymerase II transcription termination. Nat. Rev. Mol. Cell Biol. 12, 283–294 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Skourti-Stathaki, K., Kamieniarz-Gdula, K. & Proudfoot, N. J. R-loops induce repressive chromatin marks over mammalian gene terminators. Nature 516, 436–439 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ginno, P. A., Lott, P. L., Christensen, H. C., Korf, I. & Chedin, F. R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol. Cell 45, 814–825 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ginno, P. A., Lim, Y. W., Lott, P. L., Korf, I. & Chedin, F. GC skew at the 5′ and 3′ ends of human genes links R-loop formation to epigenetic regulation and transcription termination. Genome Res. 23, 1590–1600 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Skourti-Stathaki, K. & Proudfoot, N. J. Histone 3 s10 phosphorylation: “caught in the R loop!”. Mol. Cell 52, 470–472 (2013).

    CAS  PubMed  Google Scholar 

  89. Skourti-Stathaki, K., Proudfoot, N. J. & Gromak, N. Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol. Cell 42, 794–805 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Braglia, P., Kawauchi, J. & Proudfoot, N. J. Co-transcriptional RNA cleavage provides a failsafe termination mechanism for yeast RNA polymerase I. Nucleic Acids Res. 39, 1439–1448 (2011).

    CAS  PubMed  Google Scholar 

  91. Rondon, A. G., Mischo, H. E., Kawauchi, J. & Proudfoot, N. J. Fail-safe transcriptional termination for protein-coding genes in S. cerevisiae. Mol. Cell 36, 88–98 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Duc, C., Sherstnev, A., Cole, C., Barton, G. J. & Simpson, G. G. Transcription termination and chimeric RNA formation controlled by Arabidopsis thaliana FPA. PLoS Genet. 9, e1003867 (2013).

    PubMed  PubMed Central  Google Scholar 

  93. Liu, F., Bakht, S. & Dean, C. Cotranscriptional role for Arabidopsis DICER-LIKE 4 in transcription termination. Science 335, 1621–1623 (2012). This paper shows that a Dicer-like protein associates with the 3′ region of the FCA gene and promotes cleavage of the nascent transcript.

    CAS  PubMed  Google Scholar 

  94. Wagschal, A. et al. Microprocessor, Setx, Xrn2, and Rrp6 co-operate to induce premature termination of transcription by RNAPII. Cell 150, 1147–1157 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Ying, S. Y. & Lin, S. L. Intron-derived microRNAs — fine tuning of gene functions. Gene 342, 25–28 (2004).

    CAS  PubMed  Google Scholar 

  96. Kadener, S. et al. Genome-wide identification of targets of the drosha-pasha/DGCR8 complex. RNA 15, 537–545 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Karginov, F. V. et al. Diverse endonucleolytic cleavage sites in the mammalian transcriptome depend upon microRNAs, Drosha, and additional nucleases. Mol. Cell 38, 781–788 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Han, J. et al. Posttranscriptional crossregulation between Drosha and DGCR8. Cell 136, 75–84 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Melamed, Z. et al. Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions. Mol. Cell 50, 869–881 (2013). This study finds that RNA splicing negatively regulates miRNAs at overlapping exon–intron junctions.

    CAS  PubMed  Google Scholar 

  100. Havens, M. A., Reich, A. A. & Hastings, M. L. Drosha promotes splicing of a pre-microRNA-like alternative exon. PLoS Genet. 10, e1004312 (2014).

    PubMed  PubMed Central  Google Scholar 

  101. Auyeung, V. C., Ulitsky, I., McGeary, S. E. & Bartel, D. P. Beyond secondary structure: primary-sequence determinants license pri-miRNA hairpins for processing. Cell 152, 844–858 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Luhur, A., Chawla, G., Wu, Y. C., Li, J. & Sokol, N. S. Drosha-independent DGCR8/Pasha pathway regulates neuronal morphogenesis. Proc. Natl Acad. Sci. USA 111, 1421–1426 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Macias, S. et al. DGCR8 HITS-CLIP reveals novel functions for the Microprocessor. Nat. Struct. Mol. Biol. 19, 760–766 (2012). This work shows that mRNAs, snoRNAs and long non-coding RNAs are substrates for DGCR8.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Brameier, M., Herwig, A., Reinhardt, R., Walter, L. & Gruber, J. Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs. Nucleic Acids Res. 39, 675–686 (2011).

    CAS  PubMed  Google Scholar 

  105. Ender, C. et al. A human snoRNA with microRNA-like functions. Mol. Cell 32, 519–528 (2008).

    CAS  PubMed  Google Scholar 

  106. Taft, R. J. et al. Small RNAs derived from snoRNAs. RNA 15, 1233–1240 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Lioliou, E. et al. Global regulatory functions of the Staphylococcus aureus endoribonuclease III in gene expression. PLoS Genet. 8, e1002782 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Stead, M. B. et al. Analysis of Escherichia coli RNase E and RNase III activity in vivo using tiling microarrays. Nucleic Acids Res. 39, 3188–3203 (2011).

    CAS  PubMed  Google Scholar 

  109. Durand, S., Gilet, L. & Condon, C. The essential function of B. subtilis RNase III is to silence foreign toxin genes. PLoS Genet. 8, e1003181 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Rybak-Wolf, A. et al. A variety of dicer substrates in human and C. elegans. Cell 159, 1153–1167 (2014).

    CAS  PubMed  Google Scholar 

  111. Krol, J. et al. Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Mol. Cell 25, 575–586 (2007).

    CAS  PubMed  Google Scholar 

  112. Ciaudo, C. et al. RNAi-dependent and independent control of LINE1 accumulation and mobility in mouse embryonic stem cells. PLoS Genet. 9, e1003791 (2013).

    PubMed  PubMed Central  Google Scholar 

  113. Heras, S. R. et al. The Microprocessor controls the activity of mammalian retrotransposons. Nat. Struct. Mol. Biol. 20, 1173–1181 (2013).

    CAS  PubMed  Google Scholar 

  114. Yang, N. & Kazazian, H. H. Jr. L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nat. Struct. Mol. Biol. 13, 763–771 (2006).

    CAS  PubMed  Google Scholar 

  115. Hu, Q. et al. DICER- and AGO3-dependent generation of retinoic acid-induced DR2 Alu RNAs regulates human stem cell proliferation. Nat. Struct. Mol. Biol. 19, 1168–1175 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. White, E., Schlackow, M., Kamieniarz-Gdula, K., Proudfoot, N. J. & Gullerova, M. Human nuclear Dicer restricts the deleterious accumulation of endogenous double-stranded RNA. Nat. Struct. Mol. Biol. 21, 552–559 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Burger, K. et al. Cyclin-dependent kinase 9 links RNA polymerase II transcription to processing of ribosomal RNA. J. Biol. Chem. 288, 21173–21183 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Wu, H., Xu, H., Miraglia, L. J. & Crooke, S. T. Human RNase III is a 160-kDa protein involved in preribosomal RNA processing. J. Biol. Chem. 275, 36957–36965 (2000).

    CAS  PubMed  Google Scholar 

  119. Sinkkonen, L., Hugenschmidt, T., Filipowicz, W. & Svoboda, P. Dicer is associated with ribosomal DNA chromatin in mammalian cells. PLoS ONE 5, e12175 (2010).

    PubMed  PubMed Central  Google Scholar 

  120. Bernstein, D. A. et al. Candida albicans Dicer (CaDcr1) is required for efficient ribosomal and spliceosomal RNA maturation. Proc. Natl Acad. Sci. USA 109, 523–528 (2012).

    CAS  PubMed  Google Scholar 

  121. Liang, X. H. & Crooke, S. T. Depletion of key protein components of the RISC pathway impairs pre-ribosomal RNA processing. Nucleic Acids Res. 39, 4875–4889 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Fukunaga, R. et al. Dicer partner proteins tune the length of mature miRNAs in flies and mammals. Cell 151, 533–546 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Lee, H. Y., Zhou, K., Smith, A. M., Noland, C. L. & Doudna, J. A. Differential roles of human Dicer- binding proteins TRBP and PACT in small RNA processing. Nucleic Acids Res. 41, 6568–6576 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Flemr, M. et al. A retrotransposon-driven dicer isoform directs endogenous small interfering RNA production in mouse oocytes. Cell 155, 807–816 (2013). This study finds that the Dicer(O) isoform shows high dsRNA processivity.

    CAS  PubMed  Google Scholar 

  125. Murchison, E. P. et al. Critical roles for Dicer in the female germline. Genes Dev. 21, 682–693 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Tam, O. H. et al. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453, 534–538 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Watanabe, T. et al. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453, 539–543 (2008).

    CAS  PubMed  Google Scholar 

  128. Sawh, A. N. & Duchaine, T. F. A truncated form of dicer tilts the balance of RNA interference pathways. Cell Rep. 4, 454–463 (2013).

    CAS  PubMed  Google Scholar 

  129. Nakagawa, A., Shi, Y., Kage-Nakadai, E., Mitani, S. & Xue, D. Caspase-dependent conversion of Dicer ribonuclease into a death-promoting deoxyribonuclease. Science 328, 327–334 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Ge, X. et al. A novel mechanism underlies caspase-dependent conversion of the dicer ribonuclease into a deoxyribonuclease during apoptosis. Cell Res. 24, 218–232 (2014).

    CAS  PubMed  Google Scholar 

  131. Ro, S. et al. The mitochondrial genome encodes abundant small noncoding RNAs. Cell Res. 23, 759–774 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sarkies, P. & Miska, E. A. Small RNAs break out: the molecular cell biology of mobile small RNAs. Nat. Rev. Mol. Cell Biol. 15, 525–535 (2014).

    CAS  PubMed  Google Scholar 

  133. Mochizuki, K., Fine, N. A., Fujisawa, T. & Gorovsky, M. A. Analysis of a piwi-related gene implicates small RNAs in genome rearrangement in tetrahymena. Cell 110, 689–699 (2002).

    CAS  PubMed  Google Scholar 

  134. Taverna, S. D., Coyne, R. S. & Allis, C. D. Methylation of histone H3 at lysine 9 targets programmed DNA elimination in tetrahymena. Cell 110, 701–711 (2002).

    CAS  PubMed  Google Scholar 

  135. Sandoval, P. Y., Swart, E. C., Arambasic, M. & Nowacki, M. Functional diversification of Dicer-like proteins and small RNAs required for genome sculpting. Dev. Cell 28, 174–188 (2014). This study shows a role for small RNAs in targeting DNA sequences for elimination.

    CAS  PubMed  Google Scholar 

  136. Juang, B. T. et al. Endogenous nuclear RNAi mediates behavioral adaptation to odor. Cell 154, 1010–1022 (2013). This study finds that endo-siRNAs can activate a negative feedback loop in response to environmental stimulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 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).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank N. Proudfoot for support and encouragement. This work was supported by the UK Medical Research Council Career Development Award to M.G.

Author information

Authors and Affiliations

  1. Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK

    Kaspar Burger & Monika Gullerova

Authors
  1. Kaspar Burger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monika Gullerova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Gullerova.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Small non-coding RNA types and Dicer proteins that mediate various nuclear RNAi pathways are shown together with their targeted genomic regions and sequences in selected organisms. (PDF 98 kb)

Supplementary information S2 (figure)

DNA double strand breaks (DSBs) trigger the formation of small non-coding RNA. (PDF 194 kb)

PowerPoint slides

Glossary

Guide strand

In mature, duplex small interfering RNAs (siRNAs) and microRNAs (miRNAs), the strand with intrinsic sequence characteristics that favour its association with the RNA-induced silencing complex (RISC). It is usually turned into the active siRNA or miRNA.

Passenger strand

In mature, duplex small interfering RNAs (siRNAs) and microRNAs (miRNAs), the strand with less preference for RNA-induced silencing complex (RISC) loading. It is usually quickly degraded or can turn into a miRNA*.

Mirtrons

A subclass of intronic microRNAs (miRNAs). The maturation of mirtrons requires pre-mRNA splicing and is Drosha independent.

Intronic miRNAs

A subclass of Drosha-dependent microRNAs (miRNAs) encoded in introns in Drosophila melanogaster, Caenorhabditis elegans and mammals.

Transcription start site (TSS)-miRNAs

A subclass of microRNAs (miRNAs) derived from nascent promoter transcripts. TSS-miRNA maturation requires Dicer but is independent of DiGeorge syndrome critical region 8 (DGCR8).

Pericentromeric regions

Chromosomal regions of heterochromatin that are located in close proximity to centromeres.

Cohesin

A ring-shaped multisubunit protein complex that regulates the separation of sister chromatids.

Macronucleus

An enlarged, polyploid nucleus in ciliates that is generated by direct cell division without meiosis and that disintegrates during development. It contains the somatic DNA.

Micronucleus

A small, diploid nucleus in ciliates that is required to initiate meiosis and cell conjugation. It contains the germline DNA.

DDR foci

Sites of DNA damage response (DDR) that include single-strand or double-strand DNA breaks.

DNA adenine methyltransferase identification

(DamID). A method based on the expression of a protein of interest fused to bacterial Dam methylase and on the detection of methylated DNA as a measure of its contact with the fusion protein.

CpG island

A short DNA sequence that is typical of promoter regions and that is predominantly methylated at CG dinucleotides.

GC-rich terminator elements

GC dinucleotide-rich sequences that frequently occur at certain types of transcription terminator regions.

Cassette exon

An exon that is spliced together with flanking intronic regions during alternative splicing.

Triplet repeats

Repeats causing a dynamic type of mutation characterized by expansion (or contraction), which is caused by DNA polymerase slippage during replication.

External transcribed spacer

A non-coding RNA sequence in the ribosomal primary RNA transcript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Burger, K., Gullerova, M. Swiss army knives: non-canonical functions of nuclear Drosha and Dicer. Nat Rev Mol Cell Biol 16, 417–430 (2015). https://doi.org/10.1038/nrm3994

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3994

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