Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?

MicroRNAs constitute a large family of small, approximately 21-nucleotide-long, non-coding RNAs that have emerged as key post-transcriptional regulators of gene expression in metazoans and plants. In mammals, microRNAs are predicted to control the activity of approximately 30% of all protein-coding genes, and have been shown to participate in the regulation of almost every cellular process investigated so far. By base pairing to mRNAs, microRNAs mediate translational repression or mRNA degradation. This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of microRNA function.

[1]  Identification of a wheat germ ribosome dissociation factor distinct from initiation factor eIF-3. , 1978, The Journal of biological chemistry.

[2]  Ronald W. Davis,et al.  The poly(A) binding protein is required for poly(A) shortening and 60S ribosomal subunit-dependent translation initiation , 1989, Cell.

[3]  R. W. Davis,et al.  Translation initiation and ribosomal biogenesis: involvement of a putative rRNA helicase and RPL46. , 1990, Science.

[4]  A. Gingras,et al.  Cocrystal Structure of the Messenger RNA 5′ Cap-Binding Protein (eIF4E) Bound to 7-methyl-GDP , 1997, Cell.

[5]  R. Vale,et al.  Circularization of mRNA by eukaryotic translation initiation factors. , 1998, Molecular cell.

[6]  Kausik Si,et al.  Initiation Factor Does Not Function as a Translation 6 of Mammalian Translation Initiation Factor Homologue Saccharomyces Cerevisiae The , 1998 .

[7]  G. Lucchini,et al.  The β4 Integrin Interactor p27BBP/eIF6 Is an Essential Nuclear Matrix Protein Involved in 60S Ribosomal Subunit Assembly , 1999, The Journal of cell biology.

[8]  V. Ambros,et al.  The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. , 1999, Developmental biology.

[9]  E. R. Gavis,et al.  Synthesis of the posterior determinant Nanos is spatially restricted by a novel cotranslational regulatory mechanism , 2000, Current Biology.

[10]  B. Reinhart,et al.  The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans , 2000, Nature.

[11]  T. Hobman,et al.  GERp95 Belongs to a Family of Signal-transducing Proteins and Requires Hsp90 Activity for Stability and Golgi Localization* , 2001, The Journal of Biological Chemistry.

[12]  P. Walter,et al.  Block of HAC1 mRNA Translation by Long-Range Base Pairing Is Released by Cytoplasmic Splicing upon Induction of the Unfolded Protein Response , 2001, Cell.

[13]  Kausik Si,et al.  The Saccharomyces cerevisiae TIF6 Gene Encoding Translation Initiation Factor 6 Is Required for 60S Ribosomal Subunit Biogenesis , 2001, Molecular and Cellular Biology.

[14]  E. Moss,et al.  Two genetic circuits repress the Caenorhabditis elegans heterochronic gene lin-28 after translation initiation. , 2002, Developmental biology.

[15]  D. A. Smillie,et al.  RNA helicase p54 (DDX6) is a shuttling protein involved in nuclear assembly of stored mRNP particles. , 2002, Journal of cell science.

[16]  Gary Ruvkun,et al.  Identification of many microRNAs that copurify with polyribosomes in mammalian neurons , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Phillip A Sharp,et al.  siRNAs can function as miRNAs , 2003 .

[18]  Haiwei Song,et al.  The enzymes and control of eukaryotic mRNA turnover , 2004, Nature Structural &Molecular Biology.

[19]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[20]  Artemis G Hatzigeorgiou,et al.  miRNP:mRNA association in polyribosomes in a human neuronal cell line. , 2004, RNA.

[21]  W. Filipowicz,et al.  Characterization of the interactions between mammalian PAZ PIWI domain proteins and Dicer , 2004, EMBO reports.

[22]  J. M. Thomson,et al.  Argonaute2 Is the Catalytic Engine of Mammalian RNAi , 2004, Science.

[23]  Jon R Lorsch,et al.  The molecular mechanics of eukaryotic translation. , 2003, Annual review of biochemistry.

[24]  W. Merrick.  Cap-dependent and cap-independent translation in eukaryotic systems. , 2004, Gene.

[25]  Eun-Young Choi,et al.  The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3'UTR. , 2004, Genes & development.

[26]  P. Jin,et al.  RNA and microRNAs in fragile X mental retardation , 2004, Nature Cell Biology.

[27]  W. Filipowicz,et al.  Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. , 2004, RNA.

[28]  C. Hunter,et al.  The STAR/Maxi-KH domain protein GLD-1 mediates a developmental switch in the translational control of C. elegans PAL-1 , 2004, Development.

[29]  R. Schneider,et al.  Tissue Distribution of AU-rich mRNA-binding Proteins Involved in Regulation of mRNA Decay* , 2004, Journal of Biological Chemistry.

[30]  M. Barton,et al.  MicroRNA binding sites in Arabidopsis class III HD-ZIP mRNAs are required for methylation of the template chromosome. , 2004, Developmental cell.

[31]  P. Macdonald,et al.  Localization-dependent oskar protein accumulation; control after the initiation of translation. , 2004, Developmental cell.

[32]  John G Doench,et al.  Specificity of microRNA target selection in translational repression. , 2004, Genes & development.

[33]  N. Standart,et al.  The active form of Xp54 RNA helicase in translational repression is an RNA-mediated oligomer. , 2004, Nucleic acids research.

[34]  T. Tuschl,et al.  Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. , 2004, Molecular cell.

[35]  N. Sonenberg,et al.  A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay , 2005, The Journal of cell biology.

[36]  Robert B. Russell,et al.  Principles of MicroRNATarget Recognition , 2005 .

[37]  Erik J. Sontheimer,et al.  Assembly and function of RNA silencing complexes , 2005, Nature Reviews Molecular Cell Biology.

[38]  Roy Parker,et al.  Movement of Eukaryotic mRNAs Between Polysomes and Cytoplasmic Processing Bodies , 2005, Science.

[39]  R. Russell,et al.  Principles of MicroRNA–Target Recognition , 2005, PLoS biology.

[40]  R. Heintzmann,et al.  A role for eIF4E and eIF4E-transporter in targeting mRNPs to mammalian processing bodies. , 2005, RNA.

[41]  Roy Parker,et al.  General Translational Repression by Activators of mRNA Decapping , 2005, Cell.

[42]  J. Castle,et al.  Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs , 2005, Nature.

[43]  Min Han,et al.  The developmental timing regulator AIN-1 interacts with miRISCs and may target the argonaute protein ALG-1 to cytoplasmic P bodies in C. elegans. , 2005, Molecular cell.

[44]  David I. K. Martin,et al.  MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(A) tail function. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Trevor R. Jackson,et al.  Centaurin 4 in cancer , 2005 .

[46]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[47]  Gregory J. Hannon,et al.  MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies , 2005, Nature Cell Biology.

[48]  N. Sonenberg,et al.  Regulation of cap-dependent translation by eIF4E inhibitory proteins , 2005, Nature.

[49]  J. Yates,et al.  A role for the P-body component GW182 in microRNA function , 2005, Nature Cell Biology.

[50]  Randal J. Kaufman,et al.  Stress granules and processing bodies are dynamically linked sites of mRNP remodeling , 2005, The Journal of cell biology.

[51]  D. Weil,et al.  The translational regulator CPEB1 provides a link between dcp1 bodies and stress granules , 2005, Journal of Cell Science.

[52]  W. Filipowicz,et al.  Inhibition of Translational Initiation by Let-7 MicroRNA in Human Cells , 2005, Science.

[53]  W. Filipowicz,et al.  Post-transcriptional gene silencing by siRNAs and miRNAs. , 2005, Current opinion in structural biology.

[54]  Ligang Wu,et al.  Micro-RNA Regulation of the Mammalian lin-28 Gene during Neuronal Differentiation of Embryonal Carcinoma Cells , 2005, Molecular and Cellular Biology.

[55]  Phillip D Zamore,et al.  microPrimer: the biogenesis and function of microRNA , 2005, Development.

[56]  N. Sonenberg,et al.  A New Paradigm for Translational Control: Inhibition via 5′-3′ mRNA Tethering by Bicoid and the eIF4E Cognate 4EHP , 2005, Cell.

[57]  E. Chan,et al.  Disruption of GW bodies impairs mammalian RNA interference , 2005, Nature Cell Biology.

[58]  A. Pasquinelli,et al.  Regulation by let-7 and lin-4 miRNAs Results in Target mRNA Degradation , 2005, Cell.

[59]  Isabelle Behm-Ansmant,et al.  A crucial role for GW182 and the DCP1:DCP2 decapping complex in miRNA-mediated gene silencing. , 2005, RNA.

[60]  R. Jackson.  Alternative mechanisms of initiating translation of mammalian mRNAs. , 2005, Biochemical Society transactions.

[61]  T. Tuschl,et al.  Identification of Novel Argonaute-Associated Proteins , 2005, Current Biology.

[62]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

[63]  G. Hannon,et al.  Control of translation and mRNA degradation by miRNAs and siRNAs. , 2006, Genes & development.

[64]  R. Levine,et al.  Staufen- and FMRP-Containing Neuronal RNPs Are Structurally and Functionally Related to Somatic P Bodies , 2006, Neuron.

[65]  Kaleb M. Pauley,et al.  Formation of GW bodies is a consequence of microRNA genesis , 2006, EMBO reports.

[66]  J. Pelletier,et al.  Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor 2alpha phosphorylation. , 2006, Molecular biology of the cell.

[67]  K. Ogawa,et al.  RAP55, a Cytoplasmic mRNP Component, Represses Translation in Xenopus Oocytes* , 2006, Journal of Biological Chemistry.

[68]  Anthony K. L. Leung,et al.  Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules , 2006, Proceedings of the National Academy of Sciences.

[69]  T. Rana,et al.  Translation Repression in Human Cells by MicroRNA-Induced Gene Silencing Requires RCK/p54 , 2006, PLoS biology.

[70]  Mihaela Zavolan,et al.  Inference of miRNA targets using evolutionary conservation and pathway analysis , 2007, BMC Bioinformatics.

[71]  P. Bork,et al.  mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. , 2006, Genes & development.

[72]  N. Sonenberg,et al.  Regulation of poly(A)-binding protein through PABP-interacting proteins. , 2006, Cold Spring Harbor symposia on quantitative biology.

[73]  S. Cohen,et al.  Genome-Wide Analysis of mRNAs Regulated by Drosha and Argonaute Proteins in Drosophila melanogaster , 2006, Molecular and Cellular Biology.

[74]  M. Stoffel,et al.  MicroRNAs: a new class of regulatory genes affecting metabolism. , 2006, Cell metabolism.

[75]  S. Kunes,et al.  Synaptic Protein Synthesis Associated with Memory Is Regulated by the RISC Pathway in Drosophila , 2006, Cell.

[76]  Anton J. Enright,et al.  Zebrafish MiR-430 Promotes Deadenylation and Clearance of Maternal mRNAs , 2006, Science.

[77]  D. Bartel,et al.  MicroRNAS and their regulatory roles in plants. , 2006, Annual review of plant biology.

[78]  Yang Yu,et al.  Evidence that microRNAs are associated with translating messenger RNAs in human cells , 2006, Nature Structural &Molecular Biology.

[79]  W. Filipowicz,et al.  Relief of microRNA-Mediated Translational Repression in Human Cells Subjected to Stress , 2006, Cell.

[80]  Mark Graham,et al.  miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. , 2006, Cell metabolism.

[81]  T. Hobman,et al.  Gawky is a component of cytoplasmic mRNA processing bodies required for early Drosophila development , 2006, The Journal of cell biology.

[82]  R. Plasterk,et al.  The diverse functions of microRNAs in animal development and disease. , 2006, Developmental cell.

[83]  Ligang Wu,et al.  MicroRNAs direct rapid deadenylation of mRNA. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[84]  E. Schuman,et al.  Dendritic Protein Synthesis, Synaptic Plasticity, and Memory , 2006, Cell.

[85]  K. Kosik.  The neuronal microRNA system , 2006, Nature Reviews Neuroscience.

[86]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[87]  Alexander F. Schier,et al.  Differential Regulation of Germline mRNAs in Soma and Germ Cells by Zebrafish miR-430 , 2006, Current Biology.

[88]  John G Doench,et al.  Recapitulation of short RNA-directed translational gene silencing in vitro. , 2006, Molecular cell.

[89]  P. Anderson,et al.  RNA granules , 2006, The Journal of cell biology.

[90]  Jin-Wu Nam,et al.  Genomics of microRNA. , 2006, Trends in genetics : TIG.

[91]  Mihaela Zavolan,et al.  Effects of Dicer and Argonaute down-regulation on mRNA levels in human HEK293 cells , 2006, Nucleic acids research.

[92]  Jerry Pelletier,et al.  Short RNAs repress translation after initiation in mammalian cells. , 2006, Molecular cell.

[93]  P. Sharp,et al.  Function and localization of microRNAs in mammalian cells. , 2006, Cold Spring Harbor symposia on quantitative biology.

[94]  M. Hentze,et al.  Bruno Acts as a Dual Repressor of oskar Translation, Promoting mRNA Oligomerization and Formation of Silencing Particles , 2006, Cell.

[95]  J. Richter,et al.  Human let-7a miRNA blocks protein production on actively translating polyribosomes , 2006, Nature Structural &Molecular Biology.

[96]  Michael E. Greenberg,et al.  A brain-specific microRNA regulates dendritic spine development , 2006, Nature.

[97]  Eugene Berezikov,et al.  Mammalian mirtron genes. , 2007, Molecular cell.

[98]  John G Doench,et al.  Comparison of siRNA-induced off-target RNA and protein effects. , 2007, RNA.

[99]  Zissimos Mourelatos,et al.  An mRNA m 7 G Cap Binding-like Motif withinHumanAgo2RepressesTranslation , 2007 .

[100]  M. Hentze,et al.  A conserved motif in Argonaute-interacting proteins mediates functional interactions through the Argonaute PIWI domain , 2007, Nature Structural &Molecular Biology.

[101]  G. Rubin,et al.  Global analysis of patterns of gene expression during Drosophila embryogenesis , 2007, Genome Biology.

[102]  D. Bartel,et al.  Intronic microRNA precursors that bypass Drosha processing , 2007, Nature.

[103]  Peer Bork,et al.  Target-specific requirements for enhancers of decapping in miRNA-mediated gene silencing. , 2007, Genes & development.

[104]  T. Nilsen,et al.  Mechanisms of microRNA‐mediated gene regulation , 2007, Trends in genetics : TIG.

[105]  Leemor Joshua-Tor,et al.  Slicer and the argonautes. , 2007, Nature chemical biology.

[106]  E. Lai,et al.  The Mirtron Pathway Generates microRNA-Class Regulatory RNAs in Drosophila , 2007, Cell.

[107]  Tsung-Cheng Chang,et al.  microRNAs in vertebrate physiology and human disease. , 2007, Annual review of genomics and human genetics (Print).

[108]  A. Pasquinelli,et al.  MicroRNA silencing through RISC recruitment of eIF6 , 2007, Nature.

[109]  S. Cohen,et al.  microRNA functions. , 2007, Annual review of cell and developmental biology.

[110]  M. Kiriakidou,et al.  An mRNA m7G Cap Binding-like Motif within Human Ago2 Represses Translation , 2007, Cell.

[111]  J. Kitzman,et al.  Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. , 2007, RNA.

[112]  Matthias W. Hentze,et al.  Drosophila miR2 induces pseudo-polysomes and inhibits translation initiation , 2007, Nature.

[113]  Takayuki Murata,et al.  MicroRNA Inhibition of Translation Initiation in Vitro by Targeting the Cap-Binding Complex eIF4F , 2007, Science.

[114]  Richard J Jackson,et al.  MicroRNAs repress translation of m7Gppp-capped target mRNAs in vitro by inhibiting initiation and promoting deadenylation. , 2007, Genes & development.

[115]  Roy Parker,et al.  P bodies and the control of mRNA translation and degradation. , 2007, Molecular cell.

[116]  G. Hannon,et al.  A complex system of small RNAs in the unicellular green alga Chlamydomonas reinhardtii. , 2007, Genes & development.

[117]  J. Steitz,et al.  Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR , 2007, Proceedings of the National Academy of Sciences.

[118]  Michael Kertesz,et al.  The role of site accessibility in microRNA target recognition , 2007, Nature Genetics.

[119]  E. Wentzel,et al.  A Hexanucleotide Element Directs MicroRNA Nuclear Import , 2007, Science.

[120]  Reuven Agami,et al.  RNA-Binding Protein Dnd1 Inhibits MicroRNA Access to Target mRNA , 2007, Cell.

[121]  R. Parker,et al.  Accumulation of polyadenylated mRNA, Pab1p, eIF4E, and eIF4G with P-bodies in Saccharomyces cerevisiae. , 2007, Molecular biology of the cell.

[122]  Michael B. Mathews,et al.  Translational control in biology and medicine , 2007 .

[123]  D. Baulcombe,et al.  miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii , 2007, Nature.

[124]  J. Steitz,et al.  Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation , 2007, Science.

[125]  J. Steitz,et al.  AU-Rich-Element-Mediated Upregulation of Translation by FXR1 and Argonaute 2 , 2007, Cell.

[126]  T. Rana,et al.  Illuminating the silence: understanding the structure and function of small RNAs , 2007, Nature Reviews Molecular Cell Biology.

[127]  Shigeyuki Yokoyama,et al.  Let-7 microRNA-mediated mRNA deadenylation and translational repression in a mammalian cell-free system. , 2007, Genes & development.

[128]  W. Filipowicz,et al.  Repression of protein synthesis by miRNAs: how many mechanisms? , 2007, Trends in cell biology.

[129]  J. Tazi,et al.  Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies , 2007, The Journal of cell biology.

[130]  E. Izaurralde,et al.  P bodies: at the crossroads of post-transcriptional pathways , 2007, Nature Reviews Molecular Cell Biology.

[131]  L. Lim,et al.  MicroRNA targeting specificity in mammals: determinants beyond seed pairing. , 2007, Molecular cell.

[132]  Gunter Meister,et al.  Argonaute proteins: mediators of RNA silencing. , 2007, Molecular cell.

[133]  Jialing Huang,et al.  Derepression of MicroRNA-mediated Protein Translation Inhibition by Apolipoprotein B mRNA-editing Enzyme Catalytic Polypeptide-like 3G (APOBEC3G) and Its Family Members* , 2007, Journal of Biological Chemistry.

[134]  R. Parker,et al.  Edc3p and a glutamine/asparagine-rich domain of Lsm4p function in processing body assembly in Saccharomyces cerevisiae , 2007, The Journal of cell biology.

[135]  L. Lim,et al.  Transcripts Targeted by the MicroRNA-16 Family Cooperatively Regulate Cell Cycle Progression , 2007, Molecular and Cellular Biology.

[136]  Isabelle Behm-Ansmant,et al.  P-Body Formation Is a Consequence, Not the Cause, of RNA-Mediated Gene Silencing , 2007, Molecular and Cellular Biology.

[137]  George Easow,et al.  Isolation of microRNA targets by miRNP immunopurification. , 2007, RNA.

[138]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[139]  Yi Wen Kong,et al.  How do microRNAs regulate gene expression? , 2008, Biochemical Society transactions.