Diversifying microRNA sequence and function

Nature Reviews Molecular Cell Biology

Volumn 14, Issue 8, 2013, Pages 475-488

  Ameres, Stefan L ^a   Zamore, Phillip D ^b  

^a ERICH SCHMID INSTITUTE OF MATERIALS SCIENCE   (Austria)

^b UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARGONAUTE PROTEIN; DICER; MESSENGER RNA; MICRORNA; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; RNA ISOFORM; RNA POLYMERASE II;

CYTOPLASM; GENE EXPRESSION; GENE FUNCTION; GENE SILENCING; GENE TARGETING; GENETIC HETEROGENEITY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MOLECULAR RECOGNITION; NONHUMAN; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; REVIEW; RNA SEQUENCE; RNA STABILITY;

ANIMALS; GENE EXPRESSION; GENETIC VARIATION; HUMANS; MICRORNAS; MODELS, BIOLOGICAL; RNA PROCESSING, POST-TRANSCRIPTIONAL; RNA STABILITY; TRANSCRIPTION, GENETIC;

ANIMALIA;

EID: 84880770383     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm3611     Document Type: Review

References (245)

1. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843-854 1993
2. Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855-862 1993
3. Griffiths-Jones, S., Grocock, R. J., van Dongen, S., Bateman, A. & Enright, A. J. miRBase: MicroRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 34, D140-D144 2006
4. Chiang, H. R. et al. Mammalian microRNAs: Experimental evaluation of novel and previously annotated genes. Genes Dev. 24, 992-1009 2010
5. 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
6. Bartel, D. P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 116, 281-297 2004
7. Jones-Rhoades, M. W., Bartel, D. P. & Bartel, B. MicroRNAs and their regulatory roles in plants. Annu. Rev. Plant Biol. 57, 19-53 2006
8. Grimson, A. et al. Early origins and evolution of microRNAs and Piwi-interacting RNAs in animals. Nature 455, 1193-1197 2008
9. 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
10. Kim, V. N., Han, J. & Siomi, M. C. Biogenesis of small RNAs in animals. Nature Rev. Mol. Cell Biol. 10, 126-139 2009
11. Axtell, M. J., Westholm, J. O. & Lai, E. C. Vive la différence: Biogenesis and evolution of microRNAs in plants and animals. Genome Biol. 12, 221 2011
12. Siomi, H. & Siomi, M. C. Posttranscriptional regulation of microRNA biogenesis in animals. Mol. Cell 38, 323-332 2010
13. Carthew, R. W. & Sontheimer, E. J. Origins and mechanisms of miRNAs and siRNAs. Cell 136, 642-655 2009
14. Yang, J. S. & Lai, E. C. Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Mol. Cell 43, 892-903 2011
15. Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051-4060 2004
16. Cai, X., Hagedorn, C. H. & Cullen, B. R. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10, 1957-1966 2004
17. Xie, Z. et al. Expression of Arabidopsis MIRNA genes. Plant Physiol. 138, 2145-2154 2005
18. Ozsolak, F. et al. Chromatin structure analyses identify miRNA promoters. Genes Dev. 22, 3172-3183 2008
19. Corcoran, D. L. et al. Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data. PLoS ONE 4, e5279 2009
20. Rodriguez, A., Griffiths-Jones, S., Ashurst, J. L. & Bradley, A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 14, 1902-1910 2004
21. Baskerville, S. & Bartel, D. P. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 11, 241-247 2005
22. Aboobaker, A. A., Tomancak, P., Patel, N., Rubin, G. M. & Lai, E. C. Drosophila microRNAs exhibit diverse spatial expression patterns during embryonic development. Proc. Natl Acad. Sci. USA 102, 18017-18022 2005
23. Kim, Y. K. & Kim, V. N. Processing of intronic microRNAs. EMBO J. 26, 775-783 2007
24. Ballarino, M. et al. Coupled RNA processing and transcription of intergenic primary microRNAs. Mol. Cell. Biol. 29, 5632-5638 2009
25. Kataoka, N., Fujita, M. & Ohno, M. Functional association of the Microprocessor complex with the spliceosome. Mol. Cell. Biol. 29, 3243-3254 2009
26. Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415-419 2003
27. Denli, A. M., Tops, B. B., Plasterk, R. H., Ketting, R. F. & Hannon, G. J. Processing of primary microRNAs by the Microprocessor complex. Nature 432, 231-235 2004
28. Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235-240 2004
29. Landthaler, M., Yalcin, A. & Tuschl, T. The human DiGeorge syndrome critical region gene 8 and its D. melanogaster homolog are required for miRNA biogenesis. Curr. Biol. 14, 2162-2167 2004
30. Han, J. et al. The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev. 18, 3016-3027 2004
31. Han, J. et al. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125, 887-901 2006
32. 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
33. Billy, E., Brondani, V., Zhang, H., Muller, U. & Filipowicz, W. Specific interference with gene expression induced by long, double-stranded RNA in mouse embryonal teratocarcinoma cell lines. Proc. Natl Acad. Sci. USA 98, 14428-14433 2001
34. Provost, P. et al. Ribonuclease activity and RNA binding of recombinant human Dicer. EMBO J. 21, 5864-5874 2002
35. Lee, Y., Jeon, K., Lee, J. T., Kim, S. & Kim, V. N. MicroRNA maturation: Stepwise processing and subcellular localization. EMBO J. 21, 4663-4670 2002
36. Zeng, Y. & Cullen, B. R. Sequence requirements for micro RNA processing and function in human cells. RNA 9, 112-123 2003
37. Okada, C. et al. A high-resolution structure of the pre-microRNA nuclear export machinery. Science 326, 1275-1279 2009
38. Yi, R., Qin, Y., Macara, I. G. & Cullen, B. R. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 17, 3011-3016 2003
39. Lund, E., Guttinger, S., Calado, A., Dahlberg, J. E. & Kutay, U. Nuclear export of microRNA precursors. Science 303, 95-98 2004
40. Bohnsack, M. T., Czaplinski, K. & Gorlich, D. Exportin 5 is a Ran GTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 10, 185-191 2004
41. Zeng, Y. & Cullen, B. R. Structural requirements for pre-microRNA binding and nuclear export by Exportin 5. Nucleic Acids Res. 32, 4776-4785 2004
42. 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
43. 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
44. 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
45. Ketting, R. F. et al. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 15, 2654-2659 2001
46. Lee, Y. S. et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117, 69-81 2004
47. Zhang, H., Kolb, F. A., Brondani, V., Billy, E. & Filipowicz, W. Human Dicer preferentially cleaves dsRNAs at their termini without a requirement for ATP. EMBO J. 21, 5875-5885 2002
48. Zhang, H., Kolb, F. A., Jaskiewicz, L., Westhof, E. & Filipowicz, W. Single processing center models for human Dicer and bacterial RNase III. Cell 118, 57-68 2004
49. Pase, L. et al. miR-451 regulates zebrafish erythroid maturation in vivo via its target gata2. Blood 113, 1794-1804 2009
50. Cheloufi, S., Dos Santos, C. O., Chong, M. M. & Hannon, G. J. A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature 465, 584-589 2010
51. Yang, J. S. et al. Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis. Proc. Natl Acad. Sci. USA 107, 15163-15168 2010
52. Saito, K., Ishizuka, A., Siomi, H. & Siomi, M. C. Processing of pre-microRNAs by the Dicer-1-Loquacious complex in Drosophila cells. PLoS Biol. 3, e235 2005
53. Forstemann, K. et al. Normal microRNA maturation and germ-line stem cell maintenance requires Loquacious, a double-stranded RNA-binding domain protein. PLoS Biol. 3, e236 2005
54. Jiang, F. et al. Dicer-1 and R3D1-L catalyze microRNA maturation in Drosophila. Genes Dev. 19, 1674-1679 2005
55. Fukunaga, R. et al. Dicer partner proteins tune the length of mature miRNAs in flies and mammals. Cell 151, 533-546 2012
56. Cenik, E. S. et al. Phosphate and R2D2 restrict the substrate specificity of Dicer-2, an ATP-driven ribonuclease. Mol. Cell 42, 172-184 2011
57. Chendrimada, T. P. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436, 740-744 2005
58. Haase, A. D. et al. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep. 6, 961-967 2005
59. Lee, Y. et al. The role of PACT in the RNA silencing pathway. EMBO J. 25, 522-532 2006
60. Lee, H. Y. & Doudna, J. A. TRBP alters human precursor microRNA processing in vitro. RNA 18, 2012-2019 2012
61. Czech, B. & Hannon, G. J. Small RNA sorting: Matchmaking for Argonautes. Nature Rev. Genet. 12, 19-31 2011
62. Kawamata, T. & Tomari, Y. Making RISC. Trends Biochem. Sci. 35, 368-376 2010
63. Bartel, D. P. MicroRNAs: Target recognition and regulatory functions. Cell 136, 215-233 2009
64. Grimson, A. et al. MicroRNA targeting specificity in mammals: Determinants beyond seed pairing. Mol. Cell 27, 91-105 2007
65. Forman, J. J., Legesse-Miller, A. & Coller, H. A. A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc. Natl Acad. Sci. USA 105, 14879-14884 2008
66. Gu, S., Jin, L., Zhang, F., Sarnow, P. & Kay, M. A. Biological basis for restriction of microRNA targets to the 3′ untranslated region in mammalian mRNAs. Nature Struct. Mol. Biol. 16, 144-150 2009
67. Forman, J. J. & Coller, H. A. The code within the code: MicroRNAs target coding regions. Cell Cycle 9, 1533-1541 2010
68. Farh, K. K. et al. The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 310, 1817-1821 2005
69. Stark, A., Brennecke, J., Bushati, N., Russell, R. B. & Cohen, S. M. Animal microRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution. Cell 123, 1133-1146 2005
70. 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
71. Krutzfeldt, J. et al. Silencing of microRNAs in vivo with antagomirs. Nature 438, 685-689 2005
72. Ameres, S. L. et al. Target RNA-directed trimming and tailing of small silencing RNAs. Science 328, 1534-1539 2010
73. Baccarini, A. et al. Kinetic analysis reveals the fate of a microRNA following target regulation in mammalian cells. Curr. Biol. 21, 369-376 2011
74. Xie, J. et al. Long-term, efficient inhibition of microRNA function in mice using rAAV vectors. Nature Methods 9, 403-409 2012
75. Yan, K. S. et al. Structure and conserved RNA binding of the PAZ domain. Nature 426, 468-474 2003
76. Lingel, A., Simon, B., Izaurralde, E. & Sattler, M. Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain. Nature 426, 465-469 2003
77. Lingel, A., Simon, B., Izaurralde, E. & Sattler, M. NMR assignment of the Drosophila Argonaute2 PAZ domain. J. Biomol. NMR 29, 421-422 2004
78. Lingel, A., Simon, B., Izaurralde, E. & Sattler, M. Nucleic acid 3′-end recognition by the Argonaute2 PAZ domain. Nature Struct. Mol. Biol. 11, 576-577 2004
79. Wang, Y., Sheng, G., Juranek, S., Tuschl, T. & Patel, D. J. Structure of the guide-strand-containing Argonaute silencing complex. Nature 456, 209-213 2008
80. Hsu, S-H. et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J. Clin. Invest. 122, 2871-2883 2012
81. Tsai, W-C. et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J. Clin. Invest. 122, 2884-2897 2012
82. Libri, V., Miesen, P., van Rij, R. P. & Buck, A. H. Regulation of microRNA biogenesis and turnover by animals and their viruses. Cell. Mol. Life Sci. http://dx.doi.org/10.1007/s00018-012-1257-1 2013
83. tenOever, B. R. RNA viruses and the host microRNA machinery. Nature Rev. Microbiol. 11, 169-180 2013
84. Pelisson, A., Sarot, E., Payen-Groschene, G. & Bucheton, A. A novel repeat-associated small interfering RNA-mediated silencing pathway downregulates complementary sense gypsy transcripts in somatic cells of the Drosophila ovary. J. Virol. 81, 1951-1960 2007
85. 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
86. Ameres, S. L., Hung, J. H., Xu, J., Weng, Z. & Zamore, P. D. Target RNA-directed tailing and trimming purifies the sorting of endo-siRNAs between the two Drosophila Argonaute proteins. RNA 17, 54-63 2011
87. Park, W., Li, J., Song, R., Messing, J. & Chen, X. CARPEL FACTORY, a Dicer homolog, and HEN1, a novel protein, act in microRNA metabolism in Arabidopsis thaliana. Curr. Biol. 12, 1484-1495 2002
88. Yu, B. et al. Methylation as a crucial step in plant microRNA biogenesis. Science 307, 932-935 2005
89. 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
90. Yang, Z., Ebright, Y. W., Yu, B. & Chen, X. HEN1 recognizes 21-24 nt small RNA duplexes and deposits a methyl group onto the 2′ OH of the 3′ terminal nucleotide. Nucleic Acids Res. 34, 667-675 2006
91. Abe, M. et al. WAVY LEAF1, an ortholog of Arabidopsis HEN1, regulates shoot development by maintaining microRNA and trans-acting small interfering RNA accumulation in rice. Plant Physiol. 154, 1335-1346 2010
92. Huang, Y. et al. Structural insights into mechanisms of the small RNA methyltransferase HEN1. Nature 461, 823-827 2009
93. Vilkaitis, G., Plotnikova, A. & Klimasauskas, S. Kinetic and functional analysis of the small RNA methyltransferase HEN1: The catalytic domain is essential for preferential modification of duplex RNA. RNA 16, 1935-1942 2010
94. Chatterjee, S. & Grosshans, H. Active turnover modulates mature microRNA activity in Caenorhabditis elegans. Nature 461, 546-549 2009
95. Song, E. et al. Sustained small interfering RNA-mediated human immunodeficiency virus type 1 inhibition in primary macrophages. J. Virol. 77, 7174-7181 2003
96. Chatterjee, S., Fasler, M., Bussing, I. & Grosshans, H. Target-mediated protection of endogenous microRNAs in C. elegans. Dev. Cell 20, 388-396 2011
97. Bail, S. et al. Differential regulation of microRNA stability. RNA 16, 1032-1039 2010
98. Berezikov, E. et al. Deep annotation of Drosophila melanogaster microRNAs yields insights into their processing, modification, and emergence. Genome Res. 21, 203-215 2011
99. Ruby, J. G. et al. Evolution, biogenesis, expression, and target predictions of a substantially expanded set of Drosophila microRNAs. Genome Res. 17, 1850-1864 2007
100. Wu, H. et al. miRNA profiling of naïve, effector and memory CD8 T cells. PLoS ONE 2, e1020 2007
101. 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
102. Seitz, H., Ghildiyal, M. & Zamore, P. D. Argonaute loading improves the 5′ precision of both microRNAs and their miRNA strands in flies. Curr. Biol. 18, 147-151 2008
103. Rajagopalan, R., Vaucheret, H., Trejo, J. & Bartel, D. P. A diverse and evolutionarily fluid set of microRNAs in Arabidopsis thaliana. Genes Dev. 20, 3407-3425 2006
104. Westholm, J. O., Ladewig, E., Okamura, K., Robine, N. & Lai, E. C. Common and distinct patterns of terminal modifications to mirtrons and canonical microRNAs. RNA 18, 177-192 2012
105. Czech, B. et al. Hierarchical rules for Argonaute loading in Drosophila. Mol. Cell 36, 445-456 2009
106. Okamura, K., Liu, N. & Lai, E. C. Distinct mechanisms for microRNA strand selection by Drosophila Argonautes. Mol. Cell 36, 431-444 2009
107. Ghildiyal, M., Xu, J., Seitz, H., Weng, Z. & Zamore, P. D. Sorting of Drosophila small silencing RNAs partitions microRNA*strands into the RNA interference pathway. RNA 16, 43-56 2010
108. 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
109. Babiarz, J. E., Ruby, J. G., Wang, Y., Bartel, D. P. & Blelloch, R. Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor- independent, Dicer-dependent small RNAs. Genes Dev. 22, 2773-2785 2008
110. Glazov, E. A. et al. A microRNA catalog of the developing chicken embryo identified by a deep sequencing approach. Genome Res. 18, 957-964 2008
111. 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
112. Blow, M. J. et al. RNA editing of human microRNAs. Genome Biol. 7, R27 2006
113. Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401-1414 2007
114. Kawahara, Y. et al. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315, 1137-1140 2007
115. Hundley, H. A. & Bass, B. L. ADAR editing in double-stranded UTRs and other noncoding RNA sequences. Trends Biochem. Sci. 35, 377-383 2010
116. Knight, S. W. & Bass, B. L. The role of RNA editing by ADARs in RNAi. Mol. Cell 10, 809-817 2002
117. Habig, J. W., Aruscavage, P. J. & Bass, B. L. In C. elegans, high levels of dsRNA allow RNAi in the absence of RDE-4. PLoS ONE 3, e4052 2008
118. Wu, D., Lamm, A. T. & Fire, A. Z. Competition between ADAR and RNAi pathways for an extensive class of RNA targets. Nature Struct. Mol. Biol. 18, 1094-1101 2011
119. Liu, N. et al. The exoribonuclease Nibbler controls 3′ end processing of microRNAs in Drosophila. Curr. Biol. 21, 1888-1893 2011
120. Han, B. W., Hung, J. H., Weng, Z., Zamore, P. D. & Ameres, S. L. The 3′-to-5′ exoribonuclease Nibbler shapes the 3′ ends of microRNAs bound to Drosophila Argonaute1. Curr. Biol. 21, 1878-1887 2011
121. 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
122. Ketting, R. F. & Plasterk, R. H. A genetic link between co-suppression and RNA interference in C. elegans. Nature 404, 296-298 2000
123. Grishok, A., Tabara, H. & Mello, C. C. Genetic requirements for inheritance of RNAi in C. elegans. Science 287, 2494-2497 2000
124. Sijen, T. & Plasterk, R. H. Transposon silencing in the Caenorhabditis elegans germ line by natural RNAi. Nature 426, 310-314 2003
125. Rissland, O. S., Mikulasova, A. & Norbury, C. J. Efficient RNA polyuridylation by noncanonical poly(A) polymerases. Mol. Cell. Biol. 27, 3612-3624 2007
126. Dreyfus, M. & Regnier, P. The poly(A) tail of mRNAs: Bodyguard in eukaryotes, scavenger in bacteria. Cell 111, 611-613 2002
127. Scott, D. D. & Norbury, C. J. RNA decay via 3′ uridylation. Biochim Biophys Acta 1829, 654-665 2013
128. Heo, I. et al. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation. Cell 138, 696-708 2009
129. Hagan, J. P., Piskounova, E. & Gregory, R. I. Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nature Struct. Mol. Biol. 16, 1021-1025 2009
130. Heo, I. et al. Lin28 mediates the terminal uridylation of let-7 precursor microRNA. Mol. Cell 32, 276-284 2008
131. Joo, C., Fareh, M. & Kim, V. N. Bringing single-molecule spectroscopy to macromolecular protein complexes. Trends Biochem. Sci. 38, 30-37 2013
132. Chang, H-M., Triboulet, R., Thornton, J. E. & Gregory, R. I. A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway. Nature 497, 244-248 2013
133. Heo, I. et al. Mono-uridylation of pre-microRNA as a key step in the biogenesis of group II let-7 microRNAs. Cell 151, 521-532 2012
134. Jones, M. R. et al. Zcchc11-dependent uridylation of microRNA directs cytokine expression. Nature Cell Biol. 11, 1157-1163 2009
135. 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
136. Burroughs, A. M. et al. A comprehensive survey of 3′ animal miRNA modification events and a possible role for 3′ adenylation in modulating miRNA targeting effectiveness. Genome Res. 20, 1398-1410 2010
137. Lu, S., Sun, Y. H. & Chiang, V. L. Adenylation of plant miRNAs. Nucleic Acids Res. 37, 1878-1885 2009
138. Zhao, Y. et al. The Arabidopsis nucleotidyl transferase HESO1 uridylates unmethylated small RNAs to trigger their degradation. Curr. Biol. 22, 689-694 2012
139. Ren, G., Chen, X. & Yu, B. Uridylation of miRNAs by HEN1 SUPPRESSOR1 in Arabidopsis. Curr. Biol. 22, 695-700 2012
140. Ibrahim, F. et al. Uridylation of mature miRNAs and siRNAs by the MUT68 nucleotidyltransferase promotes their degradation in Chlamydomonas. Proc. Natl Acad. Sci. USA http://dx.doi.org/10.1073/pnas.0912632107 2010
141. Ibrahim, F., Rohr, J., Jeong, W-J., Hesson, J. & Cerutti, H. Untemplated oligoadenylation promotes degradation of RISC-cleaved transcripts. Science 314, 1893 2006
142. Shen, B. & Goodman, H. M. Uridine addition after microRNA-directed cleavage. Science 306, 997 2004
143. Tang, G., Reinhart, B. J., Bartel, D. P. & Zamore, P. D. A biochemical framework for RNA silencing in plants. Genes Dev. 17, 49-63 2003
144. Mallory, A. C. et al. MicroRNA control of PHABULOSA in leaf development: Importance of pairing to the microRNA 5′ region. EMBO J. 23, 3356-3364 2004
145. Haley, B. & Zamore, P. D. Kinetic analysis of the RNAi enzyme complex. Nature Struct. Mol. Biol. 11, 599-606 2004
146. Ameres, S. L., Martinez, J. & Schroeder, R. Molecular basis for target RNA recognition and cleavage by human RISC. Cell 130, 101-112 2007
147. Wee, L., Flores-Jasso, C. F., Salomon, W. & Zamore, P. D. Argonaute divides its RNA guide into domains with distinct functions and RNA-binding properties. Cell 151, 1055-1067 2012
148. Song, J. J., Smith, S. K., Hannon, G. J. & Joshua-Tor, L. Crystal structure of Argonaute and its implications for RISC slicer activity. Science 305, 1434-1437 2004
149. Parker, J. S., Roe, S. M. & Barford, D. Structural insights into mRNA recognition from a PIWI domain-siRNA guide complex. Nature 434, 663-666 2005
150. Wang, Y. et al. Structure of an Argonaute silencing complex with a seed-containing guide DNA and target RNA duplex. Nature 456, 921-926 2008
151. Parker, J. S., Parizotto, E. A., Wang, M., Roe, S. M. & Barford, D. Enhancement of the seed-target recognition step in RNA silencing by a PIWI/MID domain protein. Mol. Cell 33, 204-214 2009
152. Schirle, N. T. & MacRae, I. J. The crystal structure of human Argonaute2. Science 336, 1037-1040 2012
153. Elkayam, E. et al. The structure of human Argonaute-2 in complex with miR-20a. Cell 150, 100-110 2012
154. Nakanishi, K., Weinberg, D. E., Bartel, D. P. & Patel, D. J. Structure of yeast Argonaute with guide RNA. Nature 486, 368-374 2012
155. Wang, Y. et al. Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes. Nature 461, 754-761 2009
156. Chi, S. W., Hannon, G. J. & Darnell, R. B. An alternative mode of microRNA target recognition. Nature Struct. Mol. Biol. 19, 321-327 2012
157. Long, D. et al. Potent effect of target structure on microRNA function. Nature Struct. Mol. Biol. 14, 287-294 2007
158. Nielsen, C. B. et al. Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. RNA 13, 1894-1910 2007
159. 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
160. Tafer, H. et al. The impact of target site accessibility on the design of effective siRNAs. Nature Biotech. 26, 578-583 2008
161. Obernosterer, G., Tafer, H. & Martinez, J. Target site effects in the RNA interference and microRNA pathways. Biochem. Soc. Trans. 36, 1216-1219 2008
162. Kedde, M. et al. RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131, 1273-1286 2007
163. 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
164. Huang, J. et al. Derepression of microRNA-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
165. Mishima, Y. et al. Zebrafish miR-1 and miR-133 shape muscle gene expression and regulate sarcomeric actin organization. Genes Dev. 23, 619-632 2009
166. Elcheva, I., Goswami, S., Noubissi, F. K. & Spiegelman, V. S. CRD-BP protects the coding region of βTrCP1 mRNA from miR-183-mediated degradation. Mol. Cell 35, 240-246 2009
167. Goswami, S. et al. MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor mRNA is inhibited by the coding region determinant-binding protein. J. Biol. Chem. 285, 20532-20540 2010
168. Jafarifar, F., Yao, P., Eswarappa, S. M. & Fox, P. L. Repression of VEGFA by CA-rich element-binding microRNAs is modulated by hnRNP L. EMBO J. 30, 1324-1334 2011
169. Toledano, H., D'Alterio, C., Czech, B., Levine, E. & Jones, D. L. The let-7-Imp axis regulates ageing of the Drosophila testis stem-cell niche. Nature 485, 605-610 2012
170. Shin, C. et al. Expanding the microRNA targeting code: Functional sites with centered pairing. Mol. Cell 38, 789-802 2010
171. Llave, C., Xie, Z., Kasschau, K. D. & Carrington, J. C. Cleavage of Scarecrow-like mRNA targets directed by a class of Arabidopsis miRNA. Science 297, 2053-2056 2002
172. Dunoyer, P., Lecellier, C. H., Parizotto, E. A., Himber, C. & Voinnet, O. Probing the microRNA and small interfering RNA pathways with virus-encoded suppressors of RNA silencing. Plant Cell 16, 1235-1250 2004
173. Souret, F. F., Kastenmayer, J. P. & Green, P. J. AtXRN4 degrades mRNA in Arabidopsis and its substrates include selected miRNA targets. Mol. Cell 15, 173-183 2004
174. German, M. A. et al. Global identification of microRNA-target RNA pairs by parallel analysis of RNA ends. Nature Biotech. 26, 941-946 2008
175. Addo-Quaye, C., Eshoo, T. W., Bartel, D. P. & Axtell, M. J. Endogenous siRNA and miRNA targets identified by sequencing of the Arabidopsis degradome. Curr. Biol. 18, 758-762 2008
176. Jones-Rhoades, M. W. & Bartel, D. P. Computational identification of plant microRNAs and their targets, including a stress-induced miRNA. Mol. Cell 14, 787-799 2004
177. Lanet, E. et al. Biochemical evidence for translational repression by Arabidopsis microRNAs. Plant Cell 21, 1762-1768 2009
178. Brodersen, P. et al. Widespread translational inhibition by plant miRNAs and siRNAs. Science 320, 1185-1190 2008
179. Yekta, S., Shih, I. H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594-596 2004
180. Davis, E. et al. RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus. Curr. Biol. 15, 743-749 2005
181. 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
182. Bagga, S. et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122, 553-563 2005
183. Jing, Q. et al. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120, 623-634 2005
184. Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769-773 2005
185. Giraldez, A. J. et al. Zebrafish miR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312, 75-79 2006
186. 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
187. Wu, L., Fan, J. & Belasco, J. G. MicroRNAs direct rapid deadenylation of mRNA. Proc. Natl Acad. Sci. USA 103, 4034-4039 2006
188. Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64-71 2008
189. Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58-63 2008
190. Guo, H., Ingolia, N. T., Weissman, J. S. & Bartel, D. P. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835-840 2010
191. Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. & Weissman, J. S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218-223 2009
192. Hendrickson, D. G. et al. Concordant regulation of translation and mRNA abundance for hundreds of targets of a human microRNA. PLoS Biol. 7, e1000238 2009
193. Bazzini, A. A., Lee, M. T. & Giraldez, A. J. Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish. Science 336, 233-237 2012
194. 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
195. 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
196. Braun, J. E., Huntzinger, E., Fauser, M. & Izaurralde, E. GW182 proteins directly recruit cytoplasmic deadenylase complexes to miRNA targets. Mol. Cell 44, 120-133 2011
197. Thermann, R. & Hentze, M. W. Drosophila miR2 induces pseudo-polysomes and inhibits translation initiation. Nature 447, 875-878 2007
198. Iwasaki, S., Kawamata, T. & Tomari, Y. Drosophila Argonaute1 and Argonaute2 employ distinct mechanisms for translational repression. Mol. Cell 34, 58-67 2009
199. Mathonnet, G. et al. MicroRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F. Science 317, 1764-1767 2007
200. Zdanowicz, A. et al. Drosophila miR2 primarily targets the m7GpppN cap structure for translational repression. Mol. Cell 35, 881-888 2009
201. Fabian, M. R. et al. Mammalian miRNA RISC recruits CAF1 and PABP to affect PABP-dependent deadenylation. Mol. Cell 35, 868-880 2009
202. Djuranovic, S., Nahvi, A. & Green, R. miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science 336, 237-240 2012
203. Bruno, I. G. et al. Identification of a microRNA that activates gene expression by repressing nonsense-mediated RNA decay. Mol. Cell 42, 500-510 2011
204. 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
205. Li, L. C. et al. Small dsRNAs induce transcriptional activation in human cells. Proc. Natl Acad. Sci. USA 103, 17337-17342 2006
206. Schwartz, J. C. et al. Antisense transcripts are targets for activating small RNAs. Nature Struct. Mol. Biol. 15, 842-848 2008
207. Jangra, R. K., Yi, M. & Lemon, S. M. DDX6 Rck/p54) is required for efficient hepatitis C virus replication but not for internal ribosome entry site-directed translation. J. Virol. 84, 6810-6824 2010
208. Jopling, C. L., Yi, M., Lancaster, A. M., Lemon, S. M. & Sarnow, P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309, 1577-1581 2005
209. Lanford, R. E. et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327, 198-201 2010
210. Vasudevan, S., Tong, Y. & Steitz, J. A. Switching from repression to activation: MicroRNAs can up-regulate translation. Science 318, 1931-1934 2007
211. Vasudevan, S. & Steitz, J. A. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell 128, 1105-1118 2007
212. Orom, U. A., Nielsen, F. C. & Lund, A. H. MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol. Cell 30, 460-471 2008
213. Li, X., Cassidy, J. J., Reinke, C. A., Fischboeck, S. & Carthew, R. W. A microRNA imparts robustness against environmental fluctuation during development. Cell 137, 273-282 2009
214. Miska, E. A. et al. Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet. 3, e215 2007
215. Seitz, H. Redefining microRNA targets. Curr. Biol. 19, 870-873 2009
216. Meister, G., Landthaler, M., Dorsett, Y. & Tuschl, T. Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 10, 544-550 2004
217. Hutvagner, G., Simard, M. J., Mello, C. C. & Zamore, P. D. Sequence-specific inhibition of small RNA function. PLoS Biol. 2, e98 2004
218. Ebert, M. S., Neilson, J. R. & Sharp, P. A. MicroRNA sponges: Competitive inhibitors of small RNAs in mammalian cells. Nature Methods 4, 721-726 2007
219. Loya, C. M., Lu, C. S., Van Vactor, D. & Fulga, T. A. Transgenic microRNA inhibition with spatiotemporal specificity in intact organisms. Nature Methods 6, 897-903 2009
220. Ebert, M. S. & Sharp, P. A. MicroRNA sponges: Progress and possibilities. RNA 16, 2043-2050 2010
221. Franco-Zorrilla, J. M. et al. Target mimicry provides a new mechanism for regulation of microRNA activity. Nature Genet. 39, 1033-1037 2007
222. Todesco, M., Rubio-Somoza, I., Paz-Ares, J. & Weigel, D. A collection of target mimics for comprehensive analysis of microRNA function in Arabidopsis thaliana. PLoS Genet. 6, e1001031 2010
223. Salmena, L., Poliseno, L., Tay, Y., Kats, L. & Pandolfi, P. P. A ceRNA hypothesis: The Rosetta stone of a hidden RNA language? Cell 146, 353-358 2011
224. Tay, Y. et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147, 344-357 2011
225. Poliseno, L. et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033-1038 2010
226. Karreth, F. A. et al. In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 147, 382-395 2011
227. Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358-369 2011
228. Sumazin, P. et al. An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell 147, 370-381 2011
229. Lim, L. P. et al. The microRNAs of Caenorhabditis elegans. Genes Dev. 17, 991-1008 2003
230. Chang, J. et al. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol. 1, 106-113 2004
231. Mullokandov, G. et al. High-throughput assessment of microRNA activity and function using microRNA sensor and decoy libraries. Nature Methods 9, 840-846 2012
232. Care, A. et al. MicroRNA-133 controls cardiac hypertrophy. Nature Med. 13, 613-618 2007
233. Gentner, B. et al. Stable knockdown of microRNA in vivo by lentiviral vectors. Nature Methods 6, 63-66 2009
234. Haraguchi, T., Ozaki, Y. & Iba, H. Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res. 37, e43 2009
235. Cazalla, D., Yario, T. & Steitz, J. Down-regulation of a host microRNA by a herpesvirus saimiri noncoding RNA. Science 328, 1563-1566 2010
236. Marcinowski, L. et al. Degradation of cellular mir-27 by a novel, highly abundant viral transcript is important for efficient virus replication in vivo. PLoS Pathog. 8, e1002510 2012
237. Libri, V. et al. Murine cytomegalovirus encodes a miR-27 inhibitor disguised as a target. Proc. Natl Acad. Sci. USA 109, 279-284 2012
238. Salzman, J., Gawad, C., Wang, P. L., Lacayo, N. & Brown, P. O. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS ONE 7, e30733 2012
239. Hansen, T. B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384-388 2013
240. Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333-338 2013
241. Hwang, H. W., Wentzel, E. A. & Mendell, J. T. A hexanucleotide element directs microRNA nuclear import. Science 315, 97-100 2007
242. Gantier, M. P. et al. Analysis of microRNA turnover in mammalian cells following Dicer1 ablation. Nucleic Acids Res. 39, 5692-5703 2011
243. van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575-579 2007
244. Rissland, O. S., Hong, S. J. & Bartel, D. P. MicroRNA destabilization enables dynamic regulation of the miR-16 family in response to cell-cycle changes. Mol. Cell 43, 993-1004 2011
245. Zhang, Z. et al. Uracils at nucleotide position 9-11 are required for the rapid turnover of miR-29 family. Nucleic Acids Res. 39, 4387-4395 2011 Economy, Family and Youth