Abstract
Since their serendipitous discovery in nematodes, microRNAs (miRNAs) have emerged as key regulators of biological processes in animals. These small RNAs form complex networks that regulate cell differentiation, development and homeostasis. Deregulation of miRNA function is associated with an increasing number of human diseases, particularly cancer. Recent discoveries have expanded our understanding of the control of miRNA function. Here, we review the mechanisms that modulate miRNA activity, stability and cellular localization through alternative processing and maturation, sequence editing, post-translational modifications of Argonaute proteins, viral factors, transport from the cytoplasm and regulation of miRNA–target interactions. We conclude by discussing intriguing, unresolved research questions.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
N6-methyladenosine (m6A) methyltransferase WTAP-mediated miR-92b-5p accelerates osteoarthritis progression
Cell Communication and Signaling Open Access 10 August 2023
-
Circulating miR-21 as a prognostic biomarker in HCC treated by CT-guided high-dose rate brachytherapy
Radiation Oncology Open Access 28 July 2023
-
Exosomal miR-184 in the aqueous humor of patients with central serous chorioretinopathy: a potential diagnostic and prognostic biomarker
Journal of Nanobiotechnology Open Access 28 July 2023
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Swarts, D. C. et al. The evolutionary journey of Argonaute proteins. Nat. Struct. Mol. Biol. 21, 743–753 (2014).
Jonas, S. & Izaurralde, E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat. Rev. Genet. 16, 421–433 (2015).
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).
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).
Pasquinelli, A. E. et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408, 86–89 (2000).
Lau, N. C., Lim, L. P., Weinstein, E. G. & Bartel, D. P. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294, 858–862 (2001).
Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001).
Lee, R. C. & Ambros, V. An extensive class of small RNAs in Caenorhabditis elegans. Science 294, 862–864 (2001).
Bernstein, E. et al. Dicer is essential for mouse development. Nat. Genet. 35, 215–217 (2003).
Chong, M. M. W. et al. Canonical and alternate functions of the microRNA biogenesis machinery. Genes Dev. 24, 1951–1960 (2010).
Pauli, A., Rinn, J. L. & Schier, A. F. Non-coding RNAs as regulators of embryogenesis. Nat. Rev. Genet. 12, 136–149 (2011).
Burger, K. & Gullerova, M. Swiss army knives: non-canonical functions of nuclear Drosha and Dicer. Nat. Rev. Mol. Cell Biol. 16, 417–430 (2015).
Kozomara, A. & Griffiths-Jones, S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42, D68–D73 (2013).
Friedman, R. C., Farh, K. K.-H., Burge, C. B. & Bartel, D. P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009).
Esteller, M. Non-coding RNAs in human disease. Nat. Rev. Genet. 12, 861–874 (2011).
Lin, S. & Gregory, R. I. MicroRNA biogenesis pathways in cancer. Nat. Rev. Cancer 15, 321–333 (2015).
Bracken, C. P., Scott, H. S. & Goodall, G. J. A network-biology perspective of microRNA function and dysfunction in cancer. Nat. Rev. Genet. 17, 719–732 (2016).
Ventura, A. et al. Targeted deletion reveals essential and overlapping functions of the miR-17~92 family of miRNA clusters. Cell 132, 875–886 (2008).
Takamizawa, J. et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64, 3753–3756 (2004).
Lu, J. et al. MicroRNA expression profiles classify human cancers. Nat. Cell Biol. 435, 834–838 (2005).
Schwarzenbach, H., Nishida, N., Calin, G. A. & Pantel, K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat. Rev. Clin. Oncol. 11, 145–156 (2014).
Wang, Y., Goodison, S., Li, X. & Hu, H. Prognostic cancer gene signatures share common regulatory motifs. Sci. Rep. 7, 1183 (2017).
Rupaimoole, R. & Slack, F. J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 16, 203–221 (2017).
Llave, C., Kasschau, K. D., Rector, M. A. & Carrington, J. C. Endogenous and silencing-associated small RNAs in plants. Plant Cell 14, 1605–1619 (2002).
Reinhart, B. J., Weinstein, E. G., Rhoades, M. W., Bartel, B. & Bartel, D. P. MicroRNAs in plants. Genes Dev. 16, 1616–1626 (2002).
Mukherjee, K., Campos, H. & Kolaczkowski, B. Evolution of animal and plant Dicers: early parallel duplications and recurrent adaptation of antiviral RNA binding in plants. Mol. Biol. Evol. 30, 627–641 (2012).
Kurihara, Y. & Watanabe, Y. Arabidopsis micro-RNA biogenesis through Dicer-like 1 protein functions. Proc. Natl Acad. Sci. USA 101, 12753–12758 (2004).
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).
Rogers, K. & Chen, X. Biogenesis, turnover, and mode of action of plant microRNAs. Plant Cell 25, 2383–2399 (2013).
Borges, F. & Martienssen, R. A. The expanding world of small RNAs in plants. Nat. Rev. Mol. Cell Biol. 16, 727–741 (2015).
Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).
Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).
Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).
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).
Bracht, J., Hunter, S., Eachus, R., Weeks, P. & Pasquinelli, A. E. Trans-splicing and polyadenylation of let-7 microRNA primary transcripts. RNA 10, 1586–1594 (2004).
Berezikov, E. Evolution of microRNA diversity and regulation in animals. Nat. Rev. Genet. 12, 846–860 (2011).
Lim, L. P. The microRNAs of Caenorhabditis elegans. Genes Dev. 17, 991–1008 (2003).
Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).
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).
Nakanishi, K., Weinberg, D. E., Bartel, D. P. & Patel, D. J. Structure of yeast Argonaute with guide RNA. Nature 486, 368–374 (2012).
Schirle, N. T. & MacRae, I. J. The crystal structure of human Argonaute2. Science 336, 1037–1040 (2012).
Sheu-Gruttadauria, J. & MacRae, I. J. Structural foundations of RNA silencing by Argonaute. J. Mol. Biol. 429, 2619–2639 (2017).
Diederichs, S. & Haber, D. A. Dual role for argonautes in MicroRNA processing and posttranscriptional regulation of microRNA expression. Cell 131, 1097–1108 (2007).
Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).
Cheloufi, S., Santos, dos, C. O., Chong, M. M. W. & Hannon, G. J. A. Dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature 465, 584–589 (2010).
Cifuentes, D. et al. A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 328, 1694–1698 (2010).
Yekta, S., Shih, I.-H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594–596 (2004).
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).
Meister, G. et al. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol. Cell 15, 185–197 (2004).
Burroughs, A. M. et al. Deep-sequencing of human Argonaute-associated small RNAs provides insight into miRNA sorting and reveals Argonaute association with RNA fragments of diverse origin. RNA Biol. 8, 158–177 (2011).
Dueck, A., Ziegler, C., Eichner, A., Berezikov, E. & Meister, G. microRNAs associated with the different human Argonaute proteins. Nucleic Acids Res. 40, 9850–9862 (2012).
Wang, D. et al. Quantitative functions of Argonaute proteins in mammalian development. Genes Dev. 26, 693–704 (2012).
Betel, D., Koppal, A., Agius, P., Sander, C. & Leslie, C. Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol. 11, R90 (2010).
Agarwal, V., Bell, G. W., Nam, J.-W. & Bartel, D. P. Predicting effective microRNA target sites in mammalian mRNAs. eLife 4, e05005 (2015).
Wong, N. & Wang, X. miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 43, D146–152 (2015).
Schirle, N. T., Sheu-Gruttadauria, J. & MacRae, I. J. Structural basis for microRNA targeting. Science 346, 608–613 (2014).
Schirle, N. T., Sheu-Gruttadauria, J., Chandradoss, S. D., Joo, C. & MacRae, I. J. Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets. eLife 4, e07646 (2015).
Chandradoss, S. D., Schirle, N. T., Szczepaniak, M., MacRae, I. J. & Joo, C. A. Dynamic search process underlies microRNA targeting. Cell 162, 96–107 (2015).
Salomon, W. E., Jolly, S. M., Moore, M. J., Zamore, P. D. & Serebrov, V. Single-molecule imaging reveals that Argonaute reshapes the binding properties of its nucleic acid guides. Cell 162, 84–95 (2015).
Klum, S. M., Chandradoss, S. D., Schirle, N. T., Joo, C. & MacRae, I. J. Helix-7 in Argonaute2 shapes the microRNA seed region for rapid target recognition. EMBO J. 37, 75–88 (2018).
Helwak, A., Kudla, G., Dudnakova, T. & Tollervey, D. Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell 153, 654–665 (2013).
Grosswendt, S. et al. Unambiguous identification of miRNA:target site interactions by different types of ligation reactions. Mol. Cell 54, 1042–1054 (2014).
Moore, M. J. et al. miRNA-target chimeras reveal miRNA 3′-end pairing as a major determinant of Argonaute target specificity. Nat. Commun. 6, 8864 (2015).
Kim, D. et al. General rules for functional microRNA targeting. Nat. Genet. 48, 1517–1526 (2016).
Grimson, A. et al. MicroRNA Targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007).
Broughton, J. P., Lovci, M. T., Huang, J. L., Yeo, G. W. & Pasquinelli, A. E. Pairing beyond the seed supports microRNA targeting specificity. Mol. Cell 64, 320–333 (2016).
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).
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).
Liu, J. et al. A role for the P-body component GW182 in microRNA function. Nat. Cell Biol. 7, 1261–1266 (2005).
Meister, G. et al. Identification of novel Argonaute-associated proteins. Curr. Biol. 15, 2149–2155 (2005).
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).
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).
Chen, C.-Y. A., Zheng, D., Xia, Z. & Shyu, A.-B. Ago–TNRC6 triggers microRNA-mediated decay by promoting two deadenylation steps. Nat. Struct. Mol. Biol. 16, 1160–1166 (2009).
Behm-Ansmant, I. mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev. 20, 1885–1898 (2006).
Chekulaeva, M. et al. miRNA repression involves GW182-mediated recruitment of CCR4–NOT through conserved W-containing motifs. Nat. Struct. Mol. Biol. 18, 1218–1226 (2011).
Fabian, M. R. et al. miRNA-mediated deadenylation is orchestrated by GW182 through two conserved motifs that interact with CCR4–NOT. Nat. Struct. Mol. Biol. 18, 1211–1217 (2011).
Braun, J. E. et al. A direct interaction between DCP1 and XRN1 couples mRNA decapping to 5′ exonucleolytic degradation. Nat. Struct. Mol. Biol. 19, 1324–1331 (2012).
Mathys, H. et al. Structural and biochemical insights to the role of the CCR4-NOT complex and DDX6 ATPase in microRNA repression. Mol. Cell 54, 751–765 (2014).
Meijer, H. A. et al. Translational repression and eIF4A2 activity are critical for microRNA-mediated gene regulation. Science 340, 82–85 (2013).
Fukaya, T., Iwakawa, H.-O. & Tomari, Y. MicroRNAs block assembly of eIF4F translation initiation complex in Drosophila. Mol. Cell 56, 67–78 (2014).
Fukao, A. et al. microRNAs trigger dissociation of eIF4AI and eIF4AII from target mRNAs in humans. Mol. Cell 56, 79–89 (2014).
Elkayam, E. et al. Multivalent recruitment of human Argonaute by GW182. Mol. Cell 67, 646–658.e3 (2017).
Kuzuoglu-Öztürk, D. et al. miRISC and the CCR4-NOT complex silence mRNA targets independently of 43S ribosomal scanning. EMBO J. 35, 1186–1203 (2016).
Eichhorn, S. W. et al. mRNA destabilization is the dominant effect of mammalian microRNAs by the time substantial repression ensues. Mol. Cell 56, 104–115 (2014).
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).
Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008).
Uhlmann, S. et al. Global microRNA level regulation of EGFR-driven cell-cycle protein network in breast cancer. Mol. Systems Biol. 8, 1–15 (2012).
Mestdagh, P. et al. The miR-17-92 microRNA cluster regulates multiple components of the TGF-β pathway in neuroblastoma. Mol. Cell 40, 762–773 (2010).
Saetrom, P. et al. Distance constraints between microRNA target sites dictate efficacy and cooperativity. Nucleic Acids Res. 35, 2333–2342 (2007).
Broderick, J. A., Salomon, W. E., Ryder, S. P., Aronin, N. & Zamore, P. D. Argonaute protein identity and pairing geometry determine cooperativity in mammalian. RNA silencing. RNA 17, 1858–1869 (2011).
Flamand, M. N., Gan, H. H., Mayya, V. K., Gunsalus, K. C. & Duchaine, T. F. A non-canonical site reveals the cooperative mechanisms of microRNA-mediated silencing. Nucleic Acids Res. 45, 7212–7225 (2017).
Tsang, J., Zhu, J. & van Oudenaarden, A. microRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol. Cell 26, 753–767 (2007).
Ebert, M. S. & Sharp, P. A. Roles for microRNAs in conferring robustness to biological processes. Cell 149, 515–524 (2012).
Kim, V. N., Han, J. & Siomi, M. C. Biogenesis of small RNAs in animals. Nat. Rev. Mol. Cell Biol. 10, 126–139 (2009).
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).
Tan, G. C. et al. 5′ isomiR variation is of functional and evolutionary importance. Nucleic Acids Res. 42, 9424–9435 (2014).
Kim, B., Jeong, K. & Kim, V. N. Genome-wide mapping of DROSHA cleavage sites on primary microRNAs and noncanonical substrates. Mol. Cell 66, 258–269.e5 (2017).
Neilsen, C. T., Goodall, G. J. & Bracken, C. P. IsomiRs – the overlooked repertoire in the dynamic microRNAome. Trends Genet. 28, 544–549 (2012).
Nishikura, K. A-To-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83–96 (2016).
Telonis, A. G., Loher, P., Jing, Y., Londin, E. & Rigoutsos, I. Beyond the one-locus-one-miRNA paradigm: microRNA isoforms enable deeper insights into breast cancer heterogeneity. Nucleic Acids Res. 43, 9158–9175 (2015).
Telonis, A. G. et al. Knowledge about the presence or absence of miRNA isoforms (isomiRs) can successfully discriminate amongst 32 TCGA cancer types. Nucleic Acids Res. 45, 2973–2985 (2017).
Wu, H., Ye, C., Ramirez, D. & Manjunath, N. Alternative processing of primary microRNA transcripts by Drosha generates 5′ end variation of mature microRNA. PLoS ONE 4, e7566 (2009).
Lee, H. Y. & Doudna, J. A. TRBP alters human precursor microRNA processing in vitro. RNA 18, 2012–2019 (2012).
Fukunaga, R. et al. Dicer partner proteins tune the length of mature miRNAs in flies and mammals. Cell 151, 533–546 (2012).
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).
Kim, Y. et al. Deletion of human tarbp2 reveals cellular microRNA targets and cell-cycle function of TRBP. Cell Rep. 9, 1061–1074 (2014).
Wilson, R. C. et al. Dicer-TRBP complex formation ensures accurate mammalian microRNA biogenesis. Mol. Cell 57, 397–407 (2015).
Llorens, F. et al. A highly expressed miR-101 isomiR is a functional silencing small RNA. BMC Genomics 14, 104 (2013).
Manzano, M., Forte, E., Raja, A. N., Schipma, M. J. & Gottwein, E. Divergent target recognition by coexpressed 5′-isomiRs of miR-142-3p and selective viral mimicry. RNA 21, 1606–1620 (2015).
Karali, M. et al. High-resolution analysis of the human retina miRNome reveals isomiR variations and novel microRNAs. Nucleic Acids Res. 44, 1525–1540 (2016).
Mercey, O. et al. Characterizing isomiR variants within the microRNA-34/449 family. FEBS Lett. 591, 693–705 (2017).
Cloonan, N. et al. MicroRNAs and their isomiRs function cooperatively to target common biological pathways. Genome Biol. 12, R126 (2011).
Yamane, D. et al. Differential hepatitis C virus RNA target site selection and host factor activities of naturally occurring miR-122 3′ variants. Nucleic Acids Res. 45, 4743–4755 (2017).
Yu, F. et al. Naturally existing isoforms of miR-222 have distinct functions. Nucleic Acids Res. 45, 11371–11385 (2017).
Salter, J. D., Bennett, R. P. & Smith, H. C. The APOBEC protein family: united by structure, divergentin function. Trends Biochem. Sci. 41, 578–594 (2016).
Blow, M. J. et al. RNA editing of human microRNAs. Genome Biol. 7, R27 (2006).
Kawahara, Y. et al. Frequency and fate of microRNA editing in human brain. Nucleic Acids Res. 36, 5270–5280 (2008).
Yang, W. et al. Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat. Struct. Mol. Biol. 13, 13–21 (2006).
Chawla, G. & Sokol, N. S. ADAR mediates differential expression of polycistronic microRNAs. Nucleic Acids Res. 42, 5245–5255 (2014).
Vesely, C. et al. ADAR2 induces reproducible changes in sequence and abundance of mature microRNAs in the mouse brain. Nucleic Acids Res. 42, 12155–12168 (2014).
Shoshan, E. et al. Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat. Cell Biol. 17, 311–321 (2015).
Kawahara, Y., Zinshteyn, B., Chendrimada, T. P., Shiekhattar, R. & Nishikura, K. RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex. EMBO Rep. 8, 763–769 (2007).
Kawahara, Y. et al. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315, 1137–1140 (2007).
Nigita, G. et al. microRNA editing in seed region aligns with cellular changes in hypoxic conditions. Nucleic Acids Res. 44, 6298–6308 (2016).
Vitsios, D. M., Davis, M. P., van Dongen, S. & Enright, A. J. Large-scale analysis of microRNA expression, epi-transcriptomic features and biogenesis. Nucleic Acids Res. 45, 1079–1090 (2016).
Paul, D. et al. A-To-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoedited in glioblastoma multiforme. Sci. Rep. 7, D195 (2017).
Tomaselli, S. et al. Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome Biol. 16, 5 (2015).
Wang, Y. et al. Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers. Genome Res. 27, 1112–1125 (2017).
Negi, V. et al. Altered expression and editing of miRNA-100 regulates iTreg differentiation. Nucleic Acids Res. 43, 8057–8065 (2015).
Luciano, D. J., Mirsky, H., Vendetti, N. J. & Maas, S. RNA editing of a miRNA precursor. RNA 10, 1174–1177 (2004).
Fernandez-Valverde, S. L., Taft, R. J. & Mattick, J. S. Dynamic isomiR regulation in Drosophila development. RNA 16, 1881–1888 (2010).
Wyman, S. K. et al. Post-transcriptional generation of miRNA variants by multiple nucleotidyl transferases contributes to miRNA transcriptome complexity. Genome Res. 21, 1450–1461 (2011).
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).
Burns, D. M., D’Ambrogio, A., Nottrott, S. & Richter, J. D. CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation. Nature 473, 105–108 (2011).
Katoh, T., Hojo, H. & Suzuki, T. Destabilization of microRNAs in human cells by 3′ deadenylation mediated by PARN and CUGBP1. Nucleic Acids Res. 43, 7521–7534 (2015).
Mansur, F. et al. Gld2-catalyzed 3′ monoadenylation of miRNAs in the hippocampus has no detectable effect on their stability or on animal behavior. RNA 22, 1492–1499 (2016).
D’Ambrogio, A., Gu, W., Udagawa, T., Mello, C. C. & Richter, J. D. Specific miRNA stabilization by Gld2-catalyzed monoadenylation. Cell Rep. 2, 1537–1545 (2012).
Boele, J. et al. PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease. Proc. Natl Acad. Sci. USA 111, 11467–11472 (2014).
Jones, M. R. et al. Zcchc11-dependent uridylation of microRNA directs cytokine expression. Nat. Cell Biol. 11, 1157–1163 (2009).
Gutiérrez-Vázquez, C. et al. 3′ Uridylation controls mature microRNA turnover during CD4 T cell activation. RNA 23, 882–891 (2017).
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).
Rüegger, S. & Großhans, H. microRNA turnover: when, how, and why. Trends Biochem. Sci. 37, 436–446 (2012).
Guo, Y. et al. Characterization of the mammalian miRNA turnover landscape. Nucleic Acids Res. 43, 2326–2341 (2015).
Marzi, M. J. et al. Degradation dynamics of microRNAs revealed by a novel pulse-chase approach. Genome Res. 26, 554–565 (2016).
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).
Monticelli, S. et al. MicroRNA profiling of the murine hematopoietic system. Genome Biol. 6, R71 (2005).
Krol, J. et al. Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microRNAs. Cell 141, 618–631 (2010).
Ameres, S. L. et al. Target RNA-directed trimming and tailing of small silencing RNAs. Science 328, 1534–1539 (2010).
la Mata, de, M. et al. Potent degradation of neuronal miRNAs induced by highly complementary targets. EMBO Rep. 16, 500–511 (2015).
Park, J. H., Shin, S.-Y. & Shin, C. Non-canonical targets destabilize microRNAs in human Argonautes. Nucleic Acids Res. 45, 1569–1583 (2017).
Haas, G. et al. Identification of factors involved in target RNA-directed microRNA degradation. Nucleic Acids Res. 44, 2873–2887 (2016).
Kleaveland, B., Shi, C. Y., Stefano, J. & Bartel, D. P. A. Network of noncoding regulatory RNAs acts in the mammalian brain. Cell 174, 350–362.e17 (2018).
Bitetti, A. et al. microRNA degradation by a conserved target RNA regulates animal behavior. Nat. Struct. Mol. Biol. 25, 244–251 (2018).
De, N. et al. Highly complementary target RNAs promote release of guide RNAs from human Argonaute2. Mol. Cell 50, 344–355 (2013).
Pitchiaya, S., Heinicke, L. A., Park, J. I., Cameron, E. L. & Walter, N. G. Resolving subcellular miRNA trafficking and turnover at single-molecule resolution. Cell Rep. 19, 630–642 (2017).
Elbarbary, R. A. et al. Tudor-SN-mediated endonucleolytic decay of human cell microRNAs promotes G1/S phase transition. Science 356, 859–862 (2017).
Salzman, D. W. et al. miR-34 activity is modulated through 5′-end phosphorylation in response to DNA damage. Nat. Commun. 7, 10954 (2016).
Zeng, Y., Sankala, H., Zhang, X. & Graves, P. R. Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies. Biochem. J. 413, 429–436 (2008).
Horman, S. R. et al. Akt-mediated phosphorylation of Argonaute 2 downregulates cleavage and upregulates translational repression of microRNA targets. Mol. Cell 50, 356–367 (2013).
Rüdel, S. et al. Phosphorylation of human Argonaute proteins affects small RNA binding. Nucleic Acids Res. 39, 2330–2343 (2011).
Bridge, K. S. et al. Argonaute utilization for miRNA silencing is determined by phosphorylation-dependent recruitment of LIM-domain-containing proteins. Cell Rep. 20, 173–187 (2017).
McKenzie, A. J. et al. KRAS-MEK signaling controls Ago2 sorting into exosomes. Cell Rep. 15, 978–987 (2016).
Lopez-Orozco, J. et al. Functional analyses of phosphorylation events in human Argonaute 2. RNA 21, 2030–2038 (2015).
Shen, J. et al. EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2. Nature 497, 383–387 (2013).
Yang, M. et al. Dephosphorylation of tyrosine 393 in argonaute 2 by protein tyrosine phosphatase 1B regulates gene silencing in oncogenic RAS-induced senescence. Mol. Cell 55, 782–790 (2014).
Ma, J.-B. et al. Structural basis for 5′-end-specific recognition of guide RNA by the A. fulgidus Piwi protein. Nature 434, 666–670 (2005).
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).
Mazumder, A., Bose, M., Chakraborty, A., Chakrabarti, S. & Bhattacharyya, S. N. A transient reversal of miRNA-mediated repression controls macrophage activation. EMBO Rep. 14, 1008–1016 (2013).
Quévillon Huberdeau, M. et al. Phosphorylation of Argonaute proteins affects mRNA binding and is essential for microRNA-guided gene silencing in vivo. EMBO J. 36, 2088–2106 (2017).
Golden, R. J. et al. An Argonaute phosphorylation cycle promotes microRNA-mediated silencing. Nature 542, 197–202 (2017).
Qi, H. H. et al. Prolyl 4-hydroxylation regulates Argonaute 2 stability. Nature 455, 421–424 (2008).
Leung, A., Todorova, T., Ando, Y. & Chang, P. Poly(ADP-ribose) regulates post-transcriptional gene regulation in the cytoplasm. RNA Biol. 9, 542–548 (2012).
Leung, A. K. L. et al. Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol. Cell 42, 489–499 (2011).
Seo, G. J. et al. Reciprocal inhibition between intracellular antiviral signaling and the RNAi machinery in mammalian cells. Cell Host Microbe 14, 435–445 (2013).
Smibert, P., Yang, J.-S., Azzam, G., Liu, J.-L. & Lai, E. C. Homeostatic control of Argonaute stability by microRNA availability. Nat. Struct. Mol. Biol. 20, 789–795 (2013).
Bronevetsky, Y. et al. T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire. J. Exp. Med. 210, 417–432 (2013).
Sahin, U., Lapaquette, P., Andrieux, A., Faure, G. & Dejean, A. Sumoylation of human Argonaute 2 at lysine-402 regulates its stability. PLoS ONE 9, e102957 (2014).
Josa-Prado, F., Henley, J. M. & Wilkinson, K. A. SUMOylation of Argonaute-2 regulates RNA interference activity. Biochem. Biophys. Res. Commun. 464, 1066–1071 (2015).
Li, S. et al. TRIM65 regulates microRNA activity by ubiquitination of TNRC6. Proc. Natl Acad. Sci. USA 111, 6970–6975 (2014).
Eystathioy, T. et al. A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles. Mol. Biol. Cell 13, 1338–1351 (2002).
Huang, K. L., Chadee, A. B., Chen, C. Y. A., Zhang, Y. & Shyu, A. B. Phosphorylation at intrinsically disordered regions of PAM2 motif-containing proteins modulates their interactions with PABPC1 and influences mRNA fate. RNA 19, 295–305 (2013).
Suzawa, M. et al. Comprehensive identification of nuclear and cytoplasmic TNRC6A-associating proteins. J. Mol. Biol. 429, 3319–3333 (2017).
Poliseno, L. et al. A coding-independent function of geneand pseudogene mRNAs regulatestumour biology. Nature 465, 1033–1038 (2010).
Ebert, M. S., Neilson, J. R. & Sharp, P. A. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat. Methods 4, 721–726 (2007).
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).
Denzler, R., Agarwal, V., Stefano, J., Bartel, D. P. & Stoffel, M. Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol. Cell 54, 766–776 (2014).
Thomson, D. W. & Dinger, M. E. Endogenous microRNA sponges: evidence and controversy. Nat. Rev. Genet. 17, 272–283 (2016).
Jens, M. & Rajewsky, N. Competition between target sites of regulators shapes post-transcriptional gene regulation. Nat. Rev. Genet. 16, 113–126 (2015).
Denzler, R. et al. Impact of MicroRNA levels, target-site complementarity, and cooperativity on competing endogenous RNA-regulated gene expression. Mol. Cell 64, 565–579 (2016).
Bosson, A. D., Zamudio, J. R. & Sharp, P. A. Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. Mol. Cell 56, 347–359 (2014).
Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).
Karreth, F. A. et al. The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. Cell 161, 319–332 (2015).
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).
Tay, Y. et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147, 344–357 (2011).
Sumazin, P. et al. An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell 147, 370–381 (2011).
Barrett, S. P. & Salzman, J. Circular RNAs: analysis, expression and potential functions. Development 143, 1838–1847 (2016).
Hansen, T. B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).
Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).
Piwecka, M. et al. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357, eaam8526 (2017).
Guo, J. U., Agarwal, V., Guo, H. & Bartel, D. P. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 15, 101 (2014).
Webster, D. P., Klenerman, P. & Dusheiko, G. M. Hepatitis C. Lancet 385, 1124–1135 (2015).
Otto, G. A. & Puglisi, J. D. The pathway of HCV IRES-mediated translation initiation. Cell 119, 369–380 (2004).
Jopling, C. L., Schütz, S. & Sarnow, P. Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome. Cell Host Microbe 4, 77–85 (2008).
Shimakami, T. et al. Stabilization of hepatitis C virus RNA by an Ago2-miR-122 complex. Proc. Natl Acad. Sci. USA 109, 941–946 (2012).
Sedano, C. D. & Sarnow, P. Hepatitis C virus subverts liver-specific miR-122 to protect the viral genome from exoribonuclease Xrn2. Cell Host Microbe 16, 257–264 (2014).
Amador-Cañizares, Y., Bernier, A., Wilson, J. A. & Sagan, S. M. miR-122 does not impact recognition of the HCV genome by innate sensors of RNA but rather protects the 5′ end from the cellular pyrophosphatases, DOM3Z and DUSP11. Nucleic Acids Res. 46, 5139–5158 (2018).
Luna, J. M. et al. Hepatitis C virus RNA functionally sequesters miR-122. Cell 160, 1099–1110 (2015).
Scheel, T. K. H. et al. A broad RNA virus survey reveals both miRNA dependence and functional sequestration. Cell Host Microbe 19, 409–423 (2016).
Bandiera, S., Pfeffer, S., Baumert, T. F. & Zeisel, M. B. miR-122 — a key factor and therapeutic target in liver disease. J. Hepatol. 62, 448–457 (2015).
Lau, C.-C. et al. Viral-human chimeric transcript predisposes risk to liver cancer development and progression. Cancer Cell 25, 335–349 (2014).
Liang, H.-W. et al. Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122. J. Hepatol. 64, 278–291 (2016).
Cazalla, D., Yario, T., Steitz, J. A. & Steitz, J. Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science 328, 1563–1566 (2010).
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).
Gorbea, C., Mosbruger, T. & Cazalla, D. A viral Sm-class RNA base-pairs with mRNAs and recruits microRNAs to inhibit apoptosis. Nature 550, 275–279 (2017).
Buck, A. H. et al. Post-transcriptional regulation of miR-27 in murine cytomegalovirus infection. RNA 16, 307–315 (2010).
Libri, V. et al. Murine cytomegalovirus encodes a miR-27 inhibitor disguised as a target. Proc. Natl Acad. Sci. USA 109, 279–284 (2012).
Lee, S. et al. Selective degradation of host microRNAs by an intergenic HCMV noncoding RNA accelerates virus production. Cell Host Microbe 13, 678–690 (2013).
Leung, A. K. L. The whereabouts of microRNA actions: cytoplasm and beyond. Trends Cell Biol. 25, 601–610 (2015).
Hwang, H.-W., Wentzel, E. A. & Mendell, J. T. A. Hexanucleotide element directs microrna nuclear import. Science 315, 97–100 (2007).
Zisoulis, D. G., Kai, Z. S., Chang, R. K. & Pasquinelli, A. E. Autoregulation of microRNA biogenesis by let-7 and Argonaute. Nature 486, 541–544 (2012).
Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008).
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).
Arroyo, J. D. et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).
Turchinovich, A., Weiz, L., Langheinz, A. & Burwinkel, B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 39, 7223–7233 (2011).
Gallo, A., Tandon, M., Alevizos, I. & Illei, G. G. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS ONE 7, e30679 (2012).
Melo, S. A. et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26, 707–721 (2014).
Fong, M. Y. et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat. Cell Biol. 17, 183–194 (2015).
Zhang, L. et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104 (2015).
Tkach, M. & Théry, C. Communication by extracellular vesicles: where we are and where we need to go. Cell 164, 1226–1232 (2016).
Chevillet, J. R. et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc. Natl Acad. Sci. USA 111, 14888–14893 (2014).
Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017).
Ahadi, A., Brennan, S., Kennedy, P. J., Hutvágner, G. & Tran, N. Long non-coding RNAs harboring miRNA seed regions are enriched in prostate cancer exosomes. Sci. Rep. 6, 24922 (2016).
Villarroya-Beltri, C. et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4, 1–10 (2013).
Santangelo, L. et al. The RNA-binding protein SYNCRIP is a component of the hepatocyte exosomal machinery controlling microRNA sorting. Cell Rep. 17, 799–808 (2016).
Shurtleff, M. J., Temoche-Diaz, M. M., Karfilis, K. V., Ri, S. & Schekman, R. Y-Box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction. eLife 5, e19276 (2016).
Teng, Y. et al. MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression. Nat. Commun. 8, 14448 (2017).
Koppers-Lalic, D. et al. Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep. 8, 1649–1658 (2014).
Zhang, L., Yang, C.-S., Varelas, X. & Monti, S. Altered RNA editing in 3′ UTR perturbs microRNA-mediated regulation of oncogenes and tumor-suppressors. Sci. Rep. 6, 23226 (2016).
Nakano, M., Fukami, T., Gotoh, S. & Nakajima, M. A-to-I RNA editing up-regulates human dihydrofolate reductase in breast cancer. J. Biol. Chem. 292, 4873–4884 (2017).
Nam, J.-W. et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol. Cell 53, 1031–1043 (2014).
Kedde, M. et al. A Pumilio-induced RNA structure switch in p27-3′ UTR controls miR-221 and miR-222 accessibility. Nat. Cell Biol. 12, 1014–1020 (2010).
Min, K.-W. et al. AUF1 facilitates microRNA-mediated gene silencing. Nucleic Acids Res. 45, 6064–6073 (2017).
Mukherjee, N. et al. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol. Cell 43, 327–339 (2011).
Ahuja, D., Goyal, A. & Ray, P. S. Interplay between RNA-binding protein HuR and microRNA-125b regulates p53 mRNA translation in response to genotoxic stress. RNA Biol. 13, 1152–1165 (2016).
Poria, D. K., Guha, A., Nandi, I. & Ray, P. S. RNA-binding protein HuR sequesters microRNA-21 to prevent translation repression of proinflammatory tumor suppressor gene programmed cell death 4. Oncogene 35, 1703–1715 (2016).
La Rocca, G. et al. In vivo, Argonaute-bound microRNAs exist predominantly in a reservoir of low molecular weight complexes not associated with mRNA. Proc. Natl Acad. Sci. USA 112, 767–772 (2015).
Ameres, S. L., Martinez, J. & Schroeder, R. Molecular basis for target RNA recognition and cleavage by human RISC. Cell 130, 101–112 (2007).
Kertesz, M., Iovino, N., Unnerstall, U., Gaul, U. & Segal, E. The role of site accessibility in microRNA target recognition. Nat. Genet. 39, 1278–1284 (2007).
Zheng, Z. et al. Target RNA secondary structure is a major determinant of miR159 efficacy. Plant Physiol. 174, 1764–1778 (2017).
Sheu-Gruttadauria, J. & MacRae, I. J. Phase transitions in the assembly and function of human miRISC. Cell 173, 946–957.e16 (2018).
Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).
Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419 (2003).
Denli, A. M., Tops, B. B. J., Plasterk, R. H. A., Ketting, R. F. & Hannon, G. J. Processing of primary microRNAs by the Microprocessor complex. Nature 432, 231–235 (2004).
Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).
Nguyen, T. A. et al. Functional anatomy of the human Microprocessor. Cell 161, 1374–1387 (2015).
Kwon, S. C. et al. Structure of human DROSHA. Cell 164, 81–90 (2016).
Nicholson, A. W. Ribonuclease III mechanisms of double-stranded RNA cleavage. WIREs RNA 5, 31–48 (2014).
Okada, C. et al. A high-resolution structure of the pre-microRNA nuclear export machinery. Science 326, 1275–1279 (2009).
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).
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).
Hutvagner, 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).
Kim, Y.-K., Kim, B. & Kim, V. N. Re-evaluation of the roles of DROSHA, Exportin 5, and DICERin microRNA biogenesis. Proc. Natl Acad. Sci. USA 113, E1881–E1889 (2016).
MacRae, I. J., Zhou, K. & Doudna, J. A. Structural determinants of RNA recognition and cleavage by Dicer. Nat. Struct. Mol. Biol. 14, 934–940 (2007).
Park, J.-E. et al. Dicer recognizes the 5′ end of RNA for efficient and accurate processing. Nature 475, 201–205 (2011).
Tsutsumi, A., Kawamata, T., Izumi, N., Seitz, H. & Tomari, Y. Recognition of the pre-miRNA structure by Drosophila Dicer-1. Nat. Struct. Mol. Biol. 18, 1153–1158 (2011).
Tian, Y. et al. A phosphate-binding pocket within the platform-PAZ-connector helix cassette of human Dicer. Mol. Cell 53, 606–616 (2014).
MacRae, I. J. et al. Structural basis for double-stranded RNA processing by Dicer. Science 311, 195–198 (2006).
Lau, P.-W. et al. The molecular architecture of human Dicer. Nat. Struct. Mol. Biol. 19, 436–440 (2012).
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).
Rand, T. A., Petersen, S., Du, F. & Wang, X. Argonaute 2 cleaves the anti-guide strand of siRNA during RISC activation. Cell 123, 621–629 (2005).
Matranga, C., Tomari, Y., Shin, C., Bartel, D. P. & Zamore, P. D. Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 123, 607–620 (2005).
Leuschner, P. J. F., Ameres, S. L., Kueng, S. & Martinez, J. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. EMBO Rep. 101, 314–320 (2006).
Schwarz, D. S. et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell 115, 199–208 (2003).
Khvorova, A., Reynolds, A. & Jayasena, S. D. Functional siRNAs and miRNAs exhibit strand bias. Cell 115, 209–216 (2003).
Suzuki, H. I. et al. Small-RNA asymmetry is directly driven by mammalian Argonautes. Nat. Struct. Mol. Biol. 22, 512–521 (2015).
Frank, F., Sonenberg, N. & Nagar, B. Structural basis for 5. Nature 465, 818–822 (2010).
van Niel, G., D’Angelo, G. & Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19, 213–228 (2018).
Acknowledgements
L.F.R.G. is supported by an Advanced Postdoc Mobility fellowship from the Swiss National Science Foundation, project number P300PA_177860. I.J.M. is supported by US National Institutes of Health grants R01-GM104475 and R01-GM115649.
Reviewer information
Nature Reviews Molecular Cell Biology thanks A. Pasquinelli and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Author information
Authors and Affiliations
Contributions
Both authors contributed to researching, discussing, writing and revising the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Related links
miRBase: https://www.mirbase.org
Supplementary information
Glossary
- Isomirs
-
Variant forms of a canonical miRNA, generated by alternative cleavage during biogenesis, RNA editing or non-templated nucleotide addition.
- Guide strand
-
The strand in the mature miRNA duplex that is loaded into an Argonaute protein and used to identify complementary sites in target mRNAs.
- Metastable
-
A stable state in a system that is not the state of least energy.
- mRNA decay
-
Controlled mRNA degradation, usually starting with deadenylation, through either 3′–5′ exonucleolytic processing or decapping and 5′–3′ exonucleolytic processing.
- Trp-binding pockets
-
AGO possesses three pockets located in the PIWI domain, which bind tryptophan and mediate the interaction with GW182.
- miRNA clusters
-
Multiple miRNAs located in close proximity on the genome and transcribed as a single primary miRNA.
- Multivalent protein interactions
-
Protein–protein interactions mediated by multiple, often fairly weak binding events or points of contact.
- Seedless targets
-
miRNA targets with considerably reduced complementarity to the miRNA seed.
- Multivesicular endosomes
-
Type of late endosome that contains intraluminal vesicles formed by budding into the lumen of the endosome. Their content can be degraded by fusion with lysosomes or released into the extracellular space through fusion with the cell membrane.
- Exosomes
-
Type of extracellular vesicle, ~50–150 nm in diameter, that contains proteins, lipids and RNA and can carry cargo to target cells.
- Stress granules
-
Following global translation shutdown during the cellular stress response, cytoplasmic granules form, which are composed of non-translating mRNAs, translation initiation factors and regulatory proteins.
- PAM2 motif
-
Poly(A) binding protein interacting motif 2 mediates the interaction between GW182 and PABP.
- miRNA sponges
-
Transcripts that contain multiple target sites for a specific miRNA and bind miRNAs, thereby derepressing the miRNA target mRNAs.
- Small nuclear RNAs
-
Small non-coding RNAs in the nucleus that form complexes with proteins and are part of the splicing machinery.
- Circulating miRNAs
-
miRNAs present in circulation and found either as AGO–miRNA complexes or as cargo of vesicles (exosomes).
Rights and permissions
About this article
Cite this article
Gebert, L.F.R., MacRae, I.J. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol 20, 21–37 (2019). https://doi.org/10.1038/s41580-018-0045-7
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41580-018-0045-7
This article is cited by
-
Therapeutic effects of engineered exosome-based miR-25 and miR-181a treatment in spinocerebellar ataxia type 3 mice by silencing ATXN3
Molecular Medicine (2023)
-
Circulating miR-21 as a prognostic biomarker in HCC treated by CT-guided high-dose rate brachytherapy
Radiation Oncology (2023)
-
Overexpression of miR-92a attenuates kidney ischemia–reperfusion injury and improves kidney preservation by inhibiting MEK4/JNK1-related autophagy
Cellular & Molecular Biology Letters (2023)
-
LINC00313 promotes the proliferation and inhibits the apoptosis of chondrocytes via regulating miR-525-5p/GDF5 axis
Journal of Orthopaedic Surgery and Research (2023)
-
SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities
Molecular Cancer (2023)
