Key Points
-
MicroRNA (miRNA) is a single-stranded RNA of ∼22 nucleotides in length, which is generated by an RNase-III-type enzyme from an endogenous transcript that contains a local hairpin structure.
-
miRNA functions as a guide molecule in post-transcriptional gene silencing, by base pairing with the target mRNAs, which leads to mRNA cleavage or translational repression. By silencing various target mRNAs, miRNAs have key roles in diverse regulatory pathways, including control of development timing, haematopoietic cell differentiation, apoptosis, cell proliferation and organ development.
-
miRNA genes belong to class II genes, which are transcribed by RNA polymerase II. A majority of miRNA loci are found in intronic regions of protein-coding or non-coding transcription units, whereas the others are found in exonic regions of non-coding transcription units.
-
In animals, miRNA genes are transcribed to generate long primary transcripts (pri-miRNAs), which are first cropped by RNase-III-type enzyme Drosha to release the hairpin intermediates (pre-miRNAs) in the nucleus. Drosha forms a large (500–650 kDa) complex, known as the Microprocessor complex, together with its essential cofactor DGCR8/Pasha, which contains two dsRNA-binding domains. Pre-miRNA then gets exported to the cytoplasm by exportin-5, which is a member of the Ran-dependent nuclear transport receptor family. Following arrival in the cytoplasm, pre-miRNAs are subjected to the second processing step, which is carried out by Dicer, the cytoplasmic RNase-III-type protein.
-
In plants that lack Drosha and DGCR8, it has been suggested that miRNA processing is executed by Dicer-like protein 1 (DCL1) in the nucleus and that nuclear export is mediated by HASTY, the exportin-5 homologue.
Abstract
The recent discovery of microRNAs (miRNAs) took many by surprise because of their unorthodox features and widespread functions. These tiny, ∼22-nucleotide, RNAs control several pathways including developmental timing, haematopoiesis, organogenesis, apoptosis, cell proliferation and possibly even tumorigenesis. Among the most pressing questions regarding this unusual class of regulatory miRNA-encoding genes is how miRNAs are produced in cells and how the genes themselves are controlled by various regulatory networks.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ambros, V. et al. A uniform system for microRNA annotation. RNA 9, 277–279 (2003).
Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
Cullen, B. R. Transcription and processing of human microRNA precursors. Mol. Cell 16, 861–865 (2004).
Lewis, B. P., Shih, I. H., Jones Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003).
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).
Bartel, D. P. & Chen, C. Z. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nature Rev. Genet. 5, 396–400 (2004).
Kim, V. N. Small RNAs: classification, biogenesis, and function. Mol. Cells 19, 1–15 (2005).
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).
Mourelatos, Z. et al. miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev. 16, 720–728 (2002).
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). This paper, together with reference 11, presents direct evidence for the pol-II-dependent transcription of miRNA genes and delineates the structure of miRNA genes.
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).
Smalheiser, N. R. EST analyses predict the existence of a population of chimeric microRNA precursor–mRNA transcripts expressed in normal human and mouse tissues. Genome Biol. 4, 403 (2003).
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). Analyses the genomic locations of miRNA genes relative to defined transcription units.
Aukerman, M. J. & Sakai, H. Regulation of flowering time and floral organ identity by a microRNA and its APETALA2-like target genes. Plant Cell 15, 2730–2741 (2003).
Tam, W. Identification and characterization of human BIC, a gene on chromosome 21 that encodes a noncoding RNA. Gene 274, 157–167 (2001).
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).
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). This article reports the discovery of the first miRNA.
Brennecke, J., Hipfner, D. R., Stark, A., Russell, R. B. & Cohen, S. M. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113, 25–36 (2003).
Lagos-Quintana, M. et al. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12, 735–739 (2002).
Aravin, A. A. et al. The small RNA profile during Drosophila melanogaster development. Dev. Cell 5, 337–350 (2003).
Krichevsky, A. M., King, K. S., Donahue, C. P., Khrapko, K. & Kosik, K. S. A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 9, 1274–1281 (2003).
Sempere, L. F., Sokol, N. S., Dubrovsky, E. B., Berger, E. M. & Ambros, V. Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and broad-Complex gene activity. Dev. Biol. 259, 9–18 (2003).
Sempere, L. F. et al. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol. 5, R13 (2004).
Calin, G. A. et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc. Natl Acad. Sci. USA 101, 11755–11760 (2004).
Liu, C. G. et al. An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc. Natl Acad. Sci. USA 101, 9740–9744 (2004).
Schmittgen, T. D., Jiang, J., Liu, Q. & Yang, L. A high-throughput method to monitor the expression of microRNA precursors. Nucleic Acids Res. 32, e43 (2004).
Babak, T., Zhang, W., Morris, Q., Blencowe, B. J. & Hughes, T. R. Probing microRNAs with microarrays: tissue specificity and functional inference. RNA 10, 1813–1819 (2004).
Barad, O. et al. MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. Genome Res. 14, 2486–2494 (2004).
Miska, E. A. et al. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol. 5, R68 (2004).
Sun, Y. et al. Development of a micro-array to detect human and mouse microRNAs and characterization of expression in human organs. Nucleic Acids Res. 32, e188 (2004).
Johnson, S. M., Lin, S. Y. & Slack, F. J. The time of appearance of the C. elegans let-7 microRNA is transcriptionally controlled utilizing a temporal regulatory element in its promoter. Dev. Biol. 259, 364–379 (2003).
Zeng, Y., Wagner, E. J. & Cullen, B. R. Both natural and designed micro RNAs can inhibit the eExpression of cognate mRNAs when expressed in human cells. Mol. Cell 9, 1327–1333 (2002).
Ohler, U., Yekta, S., Lim, L. P., Bartel, D. P. & Burge, C. B. Patterns of flanking sequence conservation and a characteristic upstream motif for microRNA gene identification. RNA 10, 1309–1322 (2004).
Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419 (2003). This paper demonstrates the function of Drosha in primary miRNA processing.
Filippov, V., Solovyev, V., Filippova, M. & Gill, S. S. A novel type of RNase III family proteins in eukaryotes. Gene 245, 213–221 (2000).
Fortin, K. R., Nicholson, R. H. & Nicholson, A. W. Mouse ribonuclease III. cDNA structure, expression analysis, and chromosomal location. BMC Genomics 3, 26 (2002).
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).
Han, J. et al. The Drosha–DGCR8 complex in primary microRNA processing. Genes Dev. 18, 3016–3027 (2004). The authors delineate the domain structure of Drosha, a class-II RNase III protein, and confirm the 'single processing centre' model.
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).
Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).
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). References 40–43 report DGCR8/Pasha as the essential cofactor for Drosha.
Zeng, Y. & Cullen, B. R. Sequence requirements for micro RNA processing and function in human cells. RNA 9, 112–123 (2003).
Zeng, Y., Yi, R. & Cullen, B. R. Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. EMBO J. 24, 138–148 (2005).
Kim, V. N. MicroRNA precursors in motion: exportin-5 mediates their nuclear export. Trends Cell Biol. 14, 156–159 (2004).
Murchison, E. P. & Hannon, G. J. miRNAs on the move: miRNA biogenesis and the RNAi machinery. Curr. Opin. Cell Biol. 16, 223–229 (2004).
Nakielny, S. & Dreyfuss, G. Transport of proteins and RNAs in and out of the nucleus. Cell 99, 677–690 (1999).
Lund, E., Guttinger, S., Calado, A., Dahlberg, J. E. & Kutay, U. Nuclear export of microRNA precursors. Science 303, 95–98 (2004).
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).
Bohnsack, M. T., Czaplinski, K. & Gorlich, D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 10, 185–191 (2004). Together with references 49 and 50, this paper shows that exportin-5 mediates the nuclear export of pre-miRNAs.
Bohnsack, M. T. et al. Exp5 exports eEF1A via tRNA from nuclei and synergizes with other transport pathways to confine translation to the cytoplasm. EMBO J. 21, 6205–6215 (2002).
Calado, A., Treichel, N., Muller, E. C., Otto, A. & Kutay, U. Exportin-5-mediated nuclear export of eukaryotic elongation factor 1A and tRNA. EMBO J. 21, 6216–6224 (2002).
Lim, L. P. et al. The microRNAs of Caenorhabditis elegans. Genes Dev. 2, 991–1008 (2003).
Gwizdek, C. et al. Exportin-5 mediates nuclear export of minihelix-containing RNAs. J. Biol. Chem. 278, 5505–5508 (2003).
Basyuk, E., Suavet, F., Doglio, A., Bordonne, R. & Bertrand, E. Human let-7 stem-loop precursors harbor features of RNase III cleavage products. Nucleic Acids Res. 31, 6593–6597 (2003).
Zeng, Y. & Cullen, B. R. Structural requirements for pre-microRNA binding and nuclear export by Exportin 5. Nucleic Acids Res. 32, 4776–4785 (2004).
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).
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).
Knight, S. W. & Bass, B. L. A role for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans. Science 293, 2269–2271 (2001). References 58–62 reveal the key role of Dicer in small-RNA pathways.
Hammond, S. M., Bernstein, E., Beach, D. & Hannon, G. J. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 404, 293–296 (2000).
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).
Ma, J. B., Ye, K. & Patel, D. J. Structural basis for overhang-specific small interfering RNA recognition by the PAZ domain. Nature 429, 318–322 (2004).
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).
Song, J. J. et al. The crystal structure of the Argonaute2 PAZ domain reveals an RNA binding motif in RNAi effector complexes. Nature Struct. Biol. 10, 1026–1032 (2003).
Yan, K. S. et al. Structure and conserved RNA binding of the PAZ domain. Nature 426, 468–474 (2003).
Tabara, H., Yigit, E., Siomi, H. & Mello, C. C. The dsRNA binding protein RDE-4 interacts with RDE-1, DCR-1, and a DExH-box helicase to direct RNAi in C. elegans. Cell 109, 861–871 (2002).
Liu, Q. et al. R2D2, a bridge between the initiation and effector steps of the Drosophila RNAi pathway. Science 301, 1921–1925 (2003).
Ishizuka, A., Siomi, M. C. & Siomi, H. A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Genes Dev. 16, 2497–2508 (2002).
Caudy, A. A., Myers, M., Hannon, G. J. & Hammond, S. M. Fragile X-related protein and VIG associate with the RNA interference machinery. Genes Dev. 16, 2491–2496 (2002).
Jin, P. et al. Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nature Neurosci. 7, 113–117 (2004).
Hammond, S. M., Boettcher, S., Caudy, A. A., Kobayashi, R. & Hannon, G. J. Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293, 1146–1150 (2001).
Carmell, M. A., Xuan, Z., Zhang, M. Q. & Hannon, G. J. The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes Dev. 16, 2733–2742 (2002).
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). This paper presents a new model for the mechanism of action for RNase III proteins.
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).
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).
Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).
Meister, G. et al. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol. Cell 15, 185–197 (2004).
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).
Tomari, Y., Matranga, C., Haley, B., Martinez, N. & Zamore, P. D. A protein sensor for siRNA asymmetry. Science 306, 1377–1380 (2004).
Park, W. et al. CARPEL FACTORY, a Dicer homolog, and HEN1, a novel protein, act in microRNA metabolism in Arabidopsis thaliana. Curr. Biol. 12, 1484–1495 (2002).
Reinhart, B. J., Weinstein, E. G., Rhoades, M. W., Bartel, B. & Bartel, D. P. MicroRNAs in plants. Genes Dev. 16, 1616–1626 (2002).
Papp, I. et al. Evidence for nuclear processing of plant micro RNA and short interfering RNA precursors. Plant Physiol. 132, 1382–1390 (2003).
Kurihara, Y. & Watanabe, Y. Arabidopsis micro-RNA biogenesis through Dicer-like 1 protein functions. Proc. Natl Acad. Sci. USA 101, 12753–12758 (2004).
Xie, Z. et al. Genetic and functional diversification of small RNA pathways in plants. PLoS Biol. 2, E104 (2004).
Bollman, K. M. et al. HASTY, the Arabidopsis ortholog of exportin 5/MSN5, regulates phase change and morphogenesis. Development 130, 1493–1504 (2003).
Telfer, A. & Poethig, R. S. HASTY: a gene that regulates the timing of shoot maturation in Arabidopsis thaliana. Development 125, 1889–1898 (1998).
Park, M. Y. et al. Nuclear processing and export of microRNAs in Arabidopsis. Proc. Natl Acad. Sci. USA 102, 3691–3696 (2005).
Vazquez, F., Gasciolli, V., Crete, P. & Vaucheret, H. The nuclear dsRNA binding protein HYL1 is required for microRNA accumulation and plant development, but not posttranscriptional transgene silencing. Curr. Biol. 14, 346–351 (2004).
Han, M. H., Goud, S., Song, L. & Fedoroff, N. The Arabidopsis double-stranded RNA-binding protein HYL1 plays a role in microRNA-mediated gene regulation. Proc. Natl Acad. Sci. USA 101, 1093–1098 (2004).
Boutet, S. et al. Arabidopsis HEN1. A genetic link between endogenous miRNA controlling development and siRNA controlling transgene silencing and virus resistance. Curr. Biol. 13, 843–848 (2003).
Yu, B. et al. Methylation as a crucial step in plant microRNA biogenesis. Science 307, 932–935 (2005).
Ambros, V., Lee, R. C., Lavanway, A., Williams, P. T. & Jewell, D. MicroRNAs and other tiny endogenous RNAs in C. elegans. Curr. Biol. 13, 807–818 (2003).
Hannon, G. J. & Rossi, J. J. Unlocking the potential of the human genome with RNA interference. Nature 431, 371–378 (2004).
Yi, R., Doehle, B. P., Qin, Y., Macara, I. G. & Cullen, B. R. Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs. RNA 11, 220–226 (2005).
Zeng, Y., Cai, X. & Cullen, B. R. Use of RNA polymerase II to transcribe artificial microRNAs. Methods Enzymol. 392, 371–380 (2005).
Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).
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).
Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).
Chang, S., Johnston, R. J., Jr., Frokjaer-Jensen, C., Lockery, S. & Hobert, O. MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode. Nature 430, 785–789 (2004).
Johnston, R. J. & Hobert, O. A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature 426, 845–849 (2003).
Chen, C. Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004).
Yekta, S., Shih, I. H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594–596 (2004).
Xu, P., Vernooy, S. Y., Guo, M. & Hay, B. A. The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr. Biol. 13, 790–795 (2003).
Esau, C. et al. MicroRNA-143 regulates adipocyte differentiation. J. Biol. Chem. 279, 52361–52365 (2004).
Vazquez, F. et al. Endogenous trans-acting siRNAs regulate the accumulation of Arabidopsis mRNAs. Mol. Cell 16, 69–79 (2004).
Peragine, A., Yoshikawa, M., Wu, G., Albrecht, H. L. & Poethig, R. S. SGS3 and SGS2/SDE1/RDR6 are required for juvenile development and the production of trans-acting siRNAs in Arabidopsis. Genes Dev. 18, 2368–2379 (2004).
Hamilton, A., Voinnet, O., Chappell, L. & Baulcombe, D. Two classes of short interfering RNA in RNA silencing. EMBO J. 21, 4671–4679 (2002).
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).
Mette, M. F., van der Winden, J., Matzke, M. & Matzke, A. J. Short RNAs can identify new candidate transposable element families in Arabidopsis. Plant Physiol. 130, 6–9 (2002).
Djikeng, A., Shi, H., Tschudi, C. & Ullu, E. RNA interference in Trypanosoma brucei: cloning of small interfering RNAs provides evidence for retroposon-derived 24–26-nucleotide RNAs. RNA 7, 1522–1530 (2001).
Aravin, A. A. et al. Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline. Curr. Biol. 11, 1017–1027 (2001).
Aravin, A. A. et al. Dissection of a natural RNA silencing process in the Drosophila melanogaster germ line. Mol. Cell. Biol. 24, 6742–6750 (2004).
Pal-Bhadra, M., Bhadra, U. & Birchler, J. A. RNAi related mechanisms affect both transcriptional and posttranscriptional transgene silencing in Drosophila. Mol. Cell 9, 315–327 (2002).
Hall, I. M. et al. Establishment and maintenance of a heterochromatin domain. Science 297, 2232–2237 (2002).
Reinhart, B. J. & Bartel, D. P. Small RNAs correspond to centromere heterochromatic repeats. Science 297, 1831 (2002).
Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297, 1833–1837 (2002).
Zilberman, D., Cao, X. & Jacobsen, S. E. ARGONAUTE4 control of locus-specific siRNA accumulation and DNA and histone methylation. Science 299, 716–719 (2003).
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).
Liu, Y., Mochizuki, K. & Gorovsky, M. A. Histone H3 lysine 9 methylation is required for DNA elimination in developing macronuclei in Tetrahymena. Proc. Natl Acad. Sci. USA 101, 1679–1684 (2004).
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).
Kuwabara, T., Hsieh, J., Nakashima, K., Taira, K. & Gage, F. H. A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 116, 779–793 (2004).
Calin, G. A. et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 99, 15524–15529 (2002).
Blaszczyk, J. et al. Crystallographic and modeling studies of RNase III suggest a mechanism for double-stranded RNA cleavage. Structure (Camb.) 9, 1225–1236 (2001).
Poy, M. N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004).
Acknowledgements
I am grateful to members of my laboratory, especially to Young Kook Kim for the bioinformatics analysis of the miRNA gene structure. This work was supported by a Molecular and Cellular BioDiscovery Research Program grant from the Ministry of Science and Technology and a Research Fellowship from the Ministry of Education and Human Resources Development of Korea.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Related links
Related links
DATABASES
Entrez Gene
Swiss-Prot
The miRNA Registry
FlyBase
TAIR
FURTHER INFORMATION
Glossary
- SMALL INTERFERING RNA
-
(siRNA; also known as short interfering RNA). A small (21–24 nucleotide), non-coding RNA that is generated from long double-stranded RNA. siRNAs function as guide molecules in small-RNA-mediated gene silencing.
- POLYCISTRONIC TRANSCRIPTION UNIT
-
A transcript that includes regions representing multiple, non-overlapping gene products.
- CAP STRUCTURE
-
A structure, which consists of m7GpppN (where m7G represents 7-methylguanylate, p represents a phosphate group and N represents any base), that is located at the 5′ end of eukaryotic mRNAs.
- POLY(A) TAIL
-
A homopolymeric stretch of usually 25–200 adenine nucleotides that is present at the 3′ end of most eukaryotic mRNAs.
- SMALL NUCLEOLAR RNA
-
(snoRNAs). A small RNA molecule that functions in ribosome biogenesis in the nucleolus by guiding the assembly of macromolecular complexes on the target RNA to allow site-specific modifications or processing reactions to occur.
- TRANS-SPLICING
-
Intermolecular splicing that occurs in trypanosomes and worms where a short sequence (SL RNA) is linked to the 5′ end of many pre-mRNAs.
- WW DOMAIN
-
A protein domain that binds to proline-rich regions.
- DEAD-BOX RNA HELICASE DOMAIN
-
An evolutionarily conserved domain in a family of enzymes that use ATP hydrolysis to unwind RNA duplexes. The domain is named after the DEAD (Asp-Glu-Ala-Asp) motif.
- PAZ DOMAIN
-
A conserved RNA-binding domain found in members of the Dicer and Argonaute protein families, and that preferentially interacts with the 3′ end of RNA.
- ARGONAUTE PROTEINS
-
(also known as PPD proteins). A family of proteins that are characterized by the presence of two homology domains, PAZ and PIWI. These proteins are essential for diverse small-RNA pathways.
Rights and permissions
About this article
Cite this article
Kim, V. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 6, 376–385 (2005). https://doi.org/10.1038/nrm1644
Issue Date:
DOI: https://doi.org/10.1038/nrm1644