Regulation of microRNA biogenesis and function

Summary

MicroRNAs (miRNAs) are considered as key regulators of literally all cellular pathways. Therefore, miRNA biosynthesis and their individual cellular functions must be tightly regulated as well. MiRNAs are transcribed as primary transcripts, which are processed to mature miRNAs in two consecutive maturation steps. Finally, the mature miRNA is incorporated into a miRNA-protein complex, where it directly interacts with a member of the Argonaute (Ago) protein family. The miRNA guides such protein complexes to partial complementary target sites, which are typically located in the 3’ untranslated region (UTR) of mRNAs leading to inhibition of gene expression. MiRNA activity and abundance is regulated on various levels ranging from transcription and processing to target site binding and miRNA stability. Recent advances in our understanding of how miRNA activity is regulated in mammalian cells are summarised and discussed in this review article.

Keywords

microRNAs - Dicer - Drosha - Argonaute - gene silencing

• References

• 1 Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215-233.
• 2 Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell 2009; 136: 642-655.
• 3 Orom UA, Nielsen FC, Lund AH. MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell 2008; 30: 460-471.
• 4 Tay Y, Zhang J, Thomson AM. et al. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 2008; 455: 1124-1128.
• 5 Pillai RS, Bhattacharyya SN, Filipowicz W. Repression of protein synthesis by miRNAs: how many mechanisms?. Trends Cell Biol 2007; 17: 118-126.
• 6 Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010; 11: 597-610.
• 7 Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 2011; 12: 99-110.
• 8 Guo H, Ingolia NT, Weissman JS. et al. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 2010; 466: 835-840.
• 9 Jinek M, Doudna JA. A three-dimensional view of the molecular machinery of RNA interference. Nature 2009; 457: 405-412.
• 10 Frank F, Sonenberg N, Nagar B. Structural basis for 5'-nucleotide base-specific recognition of guide RNA by human AGO2. Nature 2010; 465: 818-822.
• 11 Yuan YR, Pei Y, Ma JB. et al. Crystal Structure of A. aeolicus Argonaute, a Site-Specific DNA-Guided Endoribonuclease, Provides Insights into RISC-Mediated mRNA Cleavage. Mol Cell 2005; 19: 405-419.
• 12 Song JJ, Smith SK, Hannon GJ. et al. Crystal structure of Argonaute and its implications for RISC slicer activity. Science 2004; 305: 1434-1437.
• 13 Liu J, Carmell MA, Rivas FV. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 2004; 305: 1437-1441.
• 14 Meister G, Landthaler M, Patkaniowska A. et al. Human Argonaute2 Mediates RNA Cleavage Targeted by miRNAs and siRNAs. Mol Cell 2004; 15: 185-197.
• 15 Lim LP, Lau NC, Garrett-Engele P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433: 769-773.
• 16 Mallanna SK, Rizzino A. Emerging roles of microRNAs in the control of embryonic stem cells and the generation of induced pluripotent stem cells. Dev Biol 2010; 344: 16-25.
• 17 Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 2009; 10: 704-714.
• 18 Farazi TA, Horlings HM, Ten Hoeve JJ. et al. MicroRNA sequence and expression analysis in breast tumors by deep sequencing. Cancer Res 2011; 71: 4443-4453.
• 19 Wittmann J, Jack HM. Serum microRNAs as powerful cancer biomarkers. Biochim Biophys Acta 2010; 1806: 200-207.
• 20 Winter J, Jung S, Keller S. et al. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 2009; 11: 228-234.
• 21 Salmena L, Poliseno L, Tay Y. et al. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?. Cell 2011; 146: 353-358.
• 22 Lee Y, Kim M, Han J. et al. MicroRNA genes are transcribed by RNA polymerase II. Embo J 2004; 23: 4051-4060.
• 23 Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 2004; 10: 1957-1966.
• 24 Rodriguez A, Griffiths-Jones S, Ashurst JL. et al. Identification of mammalian microRNA host genes and transcription units. Genome Res 2004; 14: 1902-1910.
• 25 Smalheiser NR. EST analyses predict the existence of a population of chimeric microRNA precursor-mRNA transcripts expressed in normal human and mouse tissues. Genome Biol 2003; 04: 403.
• 26 Lee Y, Ahn C, Han J. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003; 425: 415-419.
• 27 Gregory RI, Yan KP, Amuthan G. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 2004; 432: 235-240.
• 28 Denli AM, Tops BB, Plasterk RH. et al. Processing of primary microRNAs by the Microprocessor complex. Nature 2004; 432: 231-235.
• 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 2004; 14: 2162-2167.
• 30 Han J, Lee Y, Yeom KH. et al. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 2006; 125: 887-901.
• 31 Fukuda T, Yamagata K, Fujiyama S. et al. DEAD-box RNA helicase subunits of the Drosha complex are required for processing of rRNA and a subset of microRNAs. Nat Cell Biol 2007; 09: 604-611.
• 32 Lund E, Guttinger S, Calado A. et al. Nuclear export of microRNA precursors. Science 2004; 303: 95-98.
• 33 Yi R, Qin Y, Macara IG. et al. Exportin-5 mediates the nuclear export of premicroRNAs and short hairpin RNAs. Genes Dev 2003; 17: 3011-3016.
• 34 Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 2004; 10: 185-191.
• 35 Grishok A, Pasquinelli AE, Conte D. et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 2001; 106: 23-34.
• 36 Macrae IJ, Zhou K, Li F. et al. Structural basis for double-stranded RNA processing by Dicer. Science 2006; 311: 195-198.
• 37 Zhang H, Kolb FA, Jaskiewicz L. et al. Single processing center models for human Dicer and bacterial RNase III. Cell 2004; 118: 57-68.
• 38 Park JE, Heo I, Tian Y. et al. Dicer recognizes the 5 ' end of RNA for efficient and accurate processing. Nature 2011; 475: 201-205.
• 39 Chendrimada T P, Gregory RI, Kumaraswamy E. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 2005; 436: 740-744.
• 40 Haase AD, Jaskiewicz L, Zhang H. et al. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep 2005; 06: 961-967.
• 41 Gregory RI, Chendrimada TP, Cooch N. et al. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 2005; 123: 631-640.
• 42 Khvorova A, Reynolds A, Jayasena SD. Functional siRNAs and miRNAs exhibit strand bias. Cell 2003; 115: 209-216.
• 43 Schwarz DS, Hutvágner G, Du T. et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell 2003; 115: 199-208.
• 44 Noland CL, Ma E, Doudna JA. siRNA repositioning for guide strand selection by human Dicer complexes. Mol Cell 2011; 43: 110-121.
• 45 Ozsolak F, Poling LL, Wang Z. et al. Chromatin structure analyses identify miRNA promoters. Genes Dev 2008; 22: 3172-3183.
• 46 Raver-Shapira N, Marciano E, Meiri E. et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 2007; 26: 731-743.
• 47 He L, He X, Lim LP. et al. A microRNA component of the p53 tumour suppressor network. Nature 2007; 447: 1130-1134.
• 48 Tarasov V, Jung P, Verdoodt B. et al. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 2007; 06: 1586-1593.
• 49 Chang TC, Wentzel EA, Kent OA. et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 2007; 26: 745-752.
• 50 Thomson JM, Newman M, Parker JS. et al. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev 2006; 20: 2202-2207.
• 51 Obernosterer G, Leuschner PJ, Alenius M. et al. Post-transcriptional regulation of microRNA expression. Rna 2006; 12: 1161-1167.
• 52 Lee EJ, Baek M, Gusev Y. et al. Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors. RNA 2008; 14: 35-42.
• 53 Davis BN, Hilyard AC, Lagna G. et al. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 2008; 454: 56-61.
• 54 Davis BN, Hilyard AC, Nguyen PH. et al. Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol Cell 2010; 39: 373-384.
• 55 Suzuki HI, Yamagata K, Sugimoto K. et al. Modulation of microRNA processing by p53. Nature 2009; 460: 529-533.
• 56 Yamagata K, Fujiyama S, Ito S. et al. Maturation of micro RNA is hormonally regulated by a nuclear receptor. Mol Cell 2009; 36: 340-347.
• 57 Trabucchi M, Briata P, Garcia-Mayoral M. et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature 2009; 459: 1010-1014.
• 58 Zhang X, Wan G, Berger FG. et al. The ATM kinase induces microRNA biogenesis in the DNA damage response. Mol Cell 2011; 41: 371-383.
• 59 Michlewski G, Caceres JF. Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis. Nat Struct Mol Biol 2010; 17: 1011-1018.
• 60 Michlewski G, Guil S, Semple CA. et al. Posttranscriptional regulation of miRNAs harboring conserved terminal loops. Mol Cell 2008; 32: 383-393.
• 61 Guil S, Caceres JF. The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat Struct Mol Biol 2007; 14: 591-596.
• 62 Wu H, Sun S, Tu K. et al. A splicing-independent function of SF2/ASF in microR-NA processing. Mol Cell 2010; 38: 67-77.
• 63 Yang W, Chendrimada TP, Wang Q. et al. Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol 2006; 13: 13-21.
• 64 Okada C, Yamashita E, Lee SJ. et al. A high-resolution structure of the pre-microR-NA nuclear export machinery. Science 2009; 326: 1275-1279.
• 65 Melo SA, Moutinho C, Ropero S. et al. A genetic defect in export in-5 traps precursor microRNAs in the nucleus of cancer cells. Cancer Cell 2010; 18: 303-315.
• 66 Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science 2008; 320: 97-100.
• 67 Rybak A, Fuchs H, Smirnova L. et al. A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nat Cell Biol 2008; 10: 987-993.
• 68 Newman MA, Thomson JM, Hammond SM. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 2008; 14: 1539-1549.
• 69 Piskounova E, Viswanathan SR, Janas M. et al. Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28. J Biol Chem 2008; 283: 21310-21314.
• 70 Desjardins A, Yang A, Bouvette J. et al. Importance of the NCp7-like domain in the recognition of pre-let-7g by the pluripotency factor Lin28. Nucleic Acids Res. 2011 epub ahead of print.
• 71 Nam Y, Chen C, Gregory RI. et al. Molecular Basis for Interaction of let-7 MicroR-NAs with Lin28. Cell 2011; 147: 1080-1091.
• 72 Heo I, Joo C, Cho J. et al. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell 2008; 32: 276-284.
• 73 Newman MA, Mani V, Hammond SM. Deep sequencing of microRNA precursors reveals extensive 3' end modification. RNA 2011; 17: 1795-1803.
• 74 Heo I, Joo C, Kim YK. et al. TUT4 in concert with Lin28 suppresses microRNA biogenesis through premicroRNA uridylation. Cell 2009; 138: 696-708.
• 75 Hagan JP, Piskounova E, Gregory RI. Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat Struct Mol Biol 2009; 16: 1021-1025.
• 76 Yeom KH, Heo I, Lee J. et al. Single-molecule approach to immunoprecipitated protein complexes: insights into miRNA uridylation. EMBO Rep 2011; 12: 690-696.
• 77 Van Wynsberghe PM, Kai ZS, Massirer KB. et al. LIN-28 co-transcriptionally binds primary let-7 to regulate miRNA maturation in Caenorhabditis elegans. Nat Struct Mol Biol 2011; 18: 302-308.
• 78 Piskounova E, Polytarchou C, Thornton JE. et al. Lin28A and Lin28B Inhibit let-7 MicroRNA Biogenesis by Distinct Mechanisms. Cell 2011; 147: 1066-1079.
• 79 Rau F, Freyermuth F, Fugier C. et al. Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol 2011; 18: 840-845.
• 80 Rybak A, Fuchs H, Hadian K. et al. The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2. Nat Cell Biol 2009; 11: 1411-1420.
• 81 Bail S, Swerdel M, Liu H. et al. Differential regulation of microRNA stability. RNA 2010; 16: 1032-1039.
• 82 Krol J, Busskamp V, Markiewicz I. et al. Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microR-NAs. Cell 2010; 141: 618-631.
• 83 Chatterjee S, Grosshans H. Active turnover modulates mature microRNA activity in Caenorhabditis elegans. Nature 2009; 461: 546-549.
• 84 Rudel S, Meister G. Phosphorylation of Argonaute proteins: regulating gene regulators. Biochem J 2008; 413: e7-9.
• 85 Tay Y, Kats L, Salmena L. et al. Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs. Cell 2011; 147: 344-357.