Small RNAs: Regulators and guardians of the genome

Small non‐coding RNAs comprise several classes and sizes, but all share a unifying function in cellular physiology: epigenetic regulation of gene expression. Here, we review the salient aspects of recent studies on the biogenesis and function of three classes of small RNAs: miRNAs, siRNAs, and piRNAs. Although the mechanisms are becoming clear by which siRNA‐triggered mRNA cleavage silences genes, more studies are needed on several issues regarding miRNA‐mediated translation repression. Piwi proteins have been suggested to co‐operate in amplifying piRNA biogenesis to maintain transposon silencing in the germ line genome, but details of this process are still unknown as well as the functional consequences of piRNA expression at discrete genomic loci. J. Cell. Physiol. 213: 412–419, 2007. © 2007 Wiley‐Liss, Inc.

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

[2]  D. Moazed,et al.  Heterochromatin and Epigenetic Control of Gene Expression , 2003, Science.

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

[4]  A. Pélisson,et al.  Evidence for a piwi-Dependent RNA Silencing of the gypsy Endogenous Retrovirus by the Drosophila melanogaster flamenco Gene , 2004, Genetics.

[5]  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.

[6]  Akira Ishizuka,et al.  Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. , 2004, Genes & development.

[7]  N. Rajewsky.  microRNA target predictions in animals , 2006, Nature Genetics.

[8]  Ravi Sachidanandam,et al.  Developmentally Regulated piRNA Clusters Implicate MILI in Transposon Control , 2007, Science.

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

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

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

[12]  A. Aravin,et al.  Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline , 2001, Current Biology.

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

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

[15]  C. Sander,et al.  A novel class of small RNAs bind to MILI protein in mouse testes , 2006, Nature.

[16]  V. Kim,et al.  The role of PACT in the RNA silencing pathway , 2006, The EMBO journal.

[17]  N. Lau,et al.  Characterization of the piRNA Complex from Rat Testes , 2006, Science.

[18]  Toshiaki Watanabe,et al.  Identification and characterization of two novel classes of small RNAs in the mouse germline: retrotransposon-derived siRNAs in oocytes and germline small RNAs in testes. , 2006, Genes & development.

[19]  B. Reinhart,et al.  Small RNAs Correspond to Centromere Heterochromatic Repeats , 2002, Science.

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

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

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

[23]  Kuniaki Saito,et al.  A Slicer-Mediated Mechanism for Repeat-Associated siRNA 5' End Formation in Drosophila , 2007, Science.

[24]  M. A. Rector,et al.  Endogenous and Silencing-Associated Small RNAs in Plants Online version contains Web-only data. Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.003210. , 2002, The Plant Cell Online.

[25]  Jef D. Boeke,et al.  Mighty Piwis Defend the Germline against Genome Intruders , 2007, Cell.

[26]  Tariq M Rana,et al.  RNA helicase A interacts with RISC in human cells and functions in RISC loading. , 2007, Molecular cell.

[27]  V. Kim.  MicroRNA biogenesis: coordinated cropping and dicing , 2005, Nature Reviews Molecular Cell Biology.

[28]  T. Du,et al.  RISC Assembly Defects in the Drosophila RNAi Mutant armitage , 2004, Cell.

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

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

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

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

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

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

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

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

[37]  Franck Vazquez,et al.  Endogenous trans-acting siRNAs regulate the accumulation of Arabidopsis mRNAs. , 2004, Molecular cell.

[38]  Kuniaki Saito,et al.  Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. , 2006, Genes & development.

[39]  Ravi Sachidanandam,et al.  A germline-specific class of small RNAs binds mammalian Piwi proteins , 2006, Nature.

[40]  G. Hannon,et al.  MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. , 2007, Developmental cell.

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

[42]  V. Corces,et al.  Gypsy transposition correlates with the production of a retroviral envelope‐like protein under the tissue‐specific control of the Drosophila flamenco gene. , 1994, The EMBO journal.

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

[44]  Wei Ge,et al.  Synthetic shRNAs as potent RNAi triggers , 2005, Nature Biotechnology.

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

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

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

[48]  T. Fujisawa,et al.  Analysis of a piwi-Related Gene Implicates Small RNAs in Genome Rearrangement in Tetrahymena , 2002, Cell.

[49]  Eugene Berezikov,et al.  A Role for Piwi and piRNAs in Germ Cell Maintenance and Transposon Silencing in Zebrafish , 2007, Cell.

[50]  Kuniaki Saito,et al.  Processing of Pre-microRNAs by the Dicer-1–Loquacious Complex in Drosophila Cells , 2005, PLoS biology.

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

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

[53]  S. Jayasena,et al.  Functional siRNAs and miRNAs Exhibit Strand Bias , 2003, Cell.

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

[55]  Gang Wu,et al.  SGS3 and SGS2/SDE1/RDR6 are required for juvenile development and the production of trans-acting siRNAs in Arabidopsis. , 2004, Genes & development.

[56]  W. Deng,et al.  miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. , 2002, Developmental cell.

[57]  Manolis Kellis,et al.  Discrete Small RNA-Generating Loci as Master Regulators of Transposon Activity in Drosophila , 2007, Cell.

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

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

[60]  T. Du,et al.  Asymmetry in the Assembly of the RNAi Enzyme Complex , 2003, Cell.

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

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

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

[64]  R. Shiekhattar,et al.  TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing , 2005, Nature.

[65]  T. Rana,et al.  siRNA function in RNAi: a chemical modification analysis. , 2003, RNA.

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

[67]  T. Tuschl,et al.  Mechanisms of gene silencing by double-stranded RNA , 2004, Nature.

[68]  Sangdun Choi,et al.  Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy , 2005, Nature Biotechnology.

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

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

[71]  A. Denli,et al.  Normal microRNA Maturation and Germ-Line Stem Cell Maintenance Requires Loquacious, a Double-Stranded RNA-Binding Domain Protein , 2005, PLoS biology.

[72]  G. Hannon,et al.  Unlocking the potential of the human genome with RNA interference , 2004, Nature.

[73]  Vladimir Gvozdev,et al.  A Distinct Small RNA Pathway Silences Selfish Genetic Elements in the Germline , 2006, Science.

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

[75]  Haifan Lin,et al.  A novel class of small RNAs in mouse spermatogenic cells. , 2006, Genes & development.

[76]  Gang Wu,et al.  SGS 3 and SGS 2 / SDE 1 / RDR 6 are required for juvenile development and the production of transacting siRNAs in Arabidopsis , 2004 .

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

[78]  Olivier Voinnet,et al.  Two classes of short interfering RNA in RNA silencing , 2002, The EMBO journal.

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

[80]  Yoichi Matsuda,et al.  Mili, a mammalian member of piwi family gene, is essential for spermatogenesis , 2004, Development.

[81]  T. Rana,et al.  RNAi in human cells: basic structural and functional features of small interfering RNA. , 2002, Molecular cell.

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

[83]  H. Blau,et al.  Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies , 2005, Nature Cell Biology.

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