MicroRNAs: Biogenesis and Molecular Functions

Small regulatory RNAs are essential and ubiquitous riboregulators that are the key mediators of RNA interference (RNAi). They include microRNAs (miRNAs) and short‐interfering RNAs (siRNAs), classes of ∼22 nucleotide RNAs. miRNAs and siRNAs bind to Argonaute proteins and form effector complexes that regulate gene expression; in animals, this regulation occurs primarily at the post‐transcriptional level. In this review, we will discuss our current understanding of how miRNA and siRNAs are generated and how they function to silence gene expression, focusing on animal and, in particular, mammalian miRNAs.

[1]  V. Kim,et al.  Small RNAs just got bigger: Piwi-interacting RNAs (piRNAs) in mammalian testes. , 2006, Genes & development.

[2]  C. Llave,et al.  Cleavage of Scarecrow-like mRNA Targets Directed by a Class of Arabidopsis miRNA , 2002, Science.

[3]  Phillip D. Zamore,et al.  Sorting of Drosophila Small Silencing RNAs , 2007, Cell.

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

[5]  T. Tuschl,et al.  The Human DiGeorge Syndrome Critical Region Gene 8 and Its D. melanogaster Homolog Are Required for miRNA Biogenesis , 2004, Current Biology.

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

[7]  Ola Snøve,et al.  Distance constraints between microRNA target sites dictate efficacy and cooperativity , 2007, Nucleic acids research.

[8]  Z. Mourelatos,et al.  A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. , 2005, Genes & development.

[9]  D. Barford,et al.  Structural insights into mRNA recognition from a PIWI domain–siRNA guide complex , 2005, Nature.

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

[11]  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.

[12]  Thomas Tuschl,et al.  RISC is a 5' phosphomonoester-producing RNA endonuclease. , 2004, Genes & development.

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

[14]  B. O’Malley,et al.  DEAD-box RNA helicase subunits of the Drosha complex are required for processing of rRNA and a subset of microRNAs , 2007, Nature Cell Biology.

[15]  Diana V. Dugas,et al.  MicroRNA regulation of gene expression in plants. , 2004, Current opinion in plant biology.

[16]  E. Lai.  Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post-transcriptional regulation , 2002, Nature Genetics.

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

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

[19]  Phillip D Zamore,et al.  Perspective: machines for RNAi. , 2005, Genes & development.

[20]  A. Fire,et al.  Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans , 1998, Nature.

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

[22]  Thomas Tuschl,et al.  Structural basis for 5′-end-specific recognition of guide RNA by the A. fulgidus Piwi protein , 2005, Nature.

[23]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

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

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

[26]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[27]  Phillip D. Zamore,et al.  Drosophila microRNAs Are Sorted into Functionally Distinct Argonaute Complexes after Production by Dicer-1 , 2007, Cell.

[28]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[29]  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.

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

[31]  Byoung-Tak Zhang,et al.  Molecular Basis for the Recognition of Primary microRNAs by the Drosha-DGCR8 Complex , 2006, Cell.

[32]  T. Tuschl,et al.  RNA interference is mediated by 21- and 22-nucleotide RNAs. , 2001, Genes & development.

[33]  M. Hentze,et al.  Molecular mechanisms of translational control , 2004, Nature Reviews Molecular Cell Biology.

[34]  E. Sontheimer,et al.  Distinct Roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA Silencing Pathways , 2004, Cell.

[35]  B. Cullen,et al.  Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. , 2003, Genes & development.

[36]  A. Bradley,et al.  Identification of mammalian microRNA host genes and transcription units. , 2004, Genome research.

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

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

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

[40]  Michael Sattler,et al.  Nucleic acid 3′-end recognition by the Argonaute2 PAZ domain , 2004, Nature Structural &Molecular Biology.

[41]  G. Hannon,et al.  Crystal Structure of Argonaute and Its Implications for RISC Slicer Activity , 2004, Science.

[42]  Stijn van Dongen,et al.  miRBase: tools for microRNA genomics , 2007, Nucleic Acids Res..

[43]  A. Caudy,et al.  Argonaute2, a Link Between Genetic and Biochemical Analyses of RNAi , 2001, Science.

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

[45]  K. Czaplinski,et al.  Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. , 2004, RNA.

[46]  P. Zamore,et al.  A Protein Sensor for siRNA Asymmetry , 2004, Science.

[47]  M. Mann,et al.  miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. , 2002, Genes & development.

[48]  B. Cullen,et al.  Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. , 2004, RNA.

[49]  Yvonne Tay,et al.  A Pattern-Based Method for the Identification of MicroRNA Binding Sites and Their Corresponding Heteroduplexes , 2006, Cell.

[50]  Dang D. Long,et al.  Potent effect of target structure on microRNA function , 2007, Nature Structural &Molecular Biology.

[51]  U. Kutay,et al.  Nuclear Export of MicroRNA Precursors , 2004, Science.

[52]  D. Barford,et al.  Crystal structure of a PIWI protein suggests mechanisms for siRNA recognition and slicer activity , 2004, The EMBO journal.

[53]  Xiaodong Wang,et al.  R2D2, a Bridge Between the Initiation and Effector Steps of the Drosophila RNAi Pathway , 2003, Science.

[54]  B. Cullen,et al.  The imprinted H19 noncoding RNA is a primary microRNA precursor. , 2007, RNA.

[55]  David P. Bartel,et al.  Passenger-Strand Cleavage Facilitates Assembly of siRNA into Ago2-Containing RNAi Enzyme Complexes , 2005, Cell.

[56]  S. Guil,et al.  The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a , 2007, Nature Structural &Molecular Biology.

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

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

[59]  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.

[60]  Eric Westhof,et al.  Single Processing Center Models for Human Dicer and Bacterial RNase III , 2004, Cell.

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

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

[63]  Sheng Yin,et al.  Heme is involved in microRNA processing , 2007, Nature Structural &Molecular Biology.

[64]  Michael Q. Zhang,et al.  The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. , 2002, Genes & development.

[65]  G. Hannon,et al.  Processing of primary microRNAs by the Microprocessor complex , 2004, Nature.

[66]  G. Ruvkun,et al.  Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans , 1993, Cell.

[67]  T. Steitz,et al.  Recombining the structures of HIV integrase, RuvC and RNase H. , 1995, Structure.

[68]  D. Bartel,et al.  MicroRNA-Directed Cleavage of HOXB8 mRNA , 2004, Science.

[69]  D. Bartel,et al.  Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs , 2004, Nature Reviews Genetics.

[70]  Sanghyuk Lee,et al.  MicroRNA genes are transcribed by RNA polymerase II , 2004, The EMBO journal.

[71]  R. Russell,et al.  bantam Encodes a Developmentally Regulated microRNA that Controls Cell Proliferation and Regulates the Proapoptotic Gene hid in Drosophila , 2003, Cell.

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

[73]  Aristotelis Tsirigos,et al.  Short blocks from the noncoding parts of the human genome have instances within nearly all known genes and relate to biological processes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[74]  G. Hutvagner,et al.  A microRNA in a Multiple-Turnover RNAi Enzyme Complex , 2002, Science.

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

[76]  W. Filipowicz,et al.  Human Dicer preferentially cleaves dsRNAs at their termini without a requirement for ATP , 2002, The EMBO journal.

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

[78]  T. Tuschl,et al.  Crystal structure of A. aeolicus argonaute, a site-specific DNA-guided endoribonuclease, provides insights into RISC-mediated mRNA cleavage. , 2005, Molecular cell.

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

[80]  M. Carmell,et al.  Posttranscriptional Gene Silencing in Plants , 2006 .

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

[82]  Ji-Joon Song,et al.  Purified Argonaute2 and an siRNA form recombinant human RISC , 2005, Nature Structural &Molecular Biology.

[83]  V. Kim,et al.  The Drosha-DGCR8 complex in primary microRNA processing. , 2004, Genes & development.

[84]  A. Caudy,et al.  Role for a bidentate ribonuclease in the initiation step of RNA interference , 2001 .

[85]  V. Kim,et al.  The nuclear RNase III Drosha initiates microRNA processing , 2003, Nature.

[86]  R. Shiekhattar,et al.  Human RISC Couples MicroRNA Biogenesis and Posttranscriptional Gene Silencing , 2005, Cell.

[87]  V. Kim,et al.  MicroRNA maturation: stepwise processing and subcellular localization , 2002, The EMBO journal.

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

[89]  Nikolaus Rajewsky,et al.  Computational identification of microRNA targets , 2004, Genome Biology.

[90]  Stefan L Ameres,et al.  Molecular Basis for Target RNA Recognition and Cleavage by Human RISC , 2007, Cell.

[91]  Xiaodong Wang,et al.  Argonaute2 Cleaves the Anti-Guide Strand of siRNA during RISC Activation , 2005, Cell.

[92]  Phillip D Zamore,et al.  The RNA-Induced Silencing Complex Is a Mg2+-Dependent Endonuclease , 2004, Current Biology.

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

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

[95]  G. Hannon,et al.  The Piwi-piRNA Pathway Provides an Adaptive Defense in the Transposon Arms Race , 2007, Science.

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

[97]  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.

[98]  R. Shiekhattar,et al.  The Microprocessor complex mediates the genesis of microRNAs , 2004, Nature.

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

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

[101]  A. Hatzigeorgiou,et al.  A combined computational-experimental approach predicts human microRNA targets. , 2004, Genes & development.

[102]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

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

[104]  B. Samuelsson,et al.  Ribonuclease activity and RNA binding of recombinant human Dicer , 2002, The EMBO journal.