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• W1982131024 abstract "MicroRNAs (miRNAs) control gene expression by regulating mRNA stability and translation. Using cell-free in vitro systems, several labs have recently reported insights into the molecular mechanisms underlying miRNA-guided translational repression (Kiriakidou et al., 2007Kiriakidou M. Tan G.S. Lamprinaki S. De Planell-Saguer M. Nelson P.T. Mourelatos Z. Cell. 2007; 129: 1141-1151Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, Mathonnet et al., 2007Mathonnet G. Fabian M.R. Svitkin Y.V. Parsyan A. Huck L. Murata T. Biffo S. Merrick W.C. Darzynkiewicz E. Pillai R.S. et al.Science. 2007; (Published online July 26, 2007)https://doi.org/10.1126/science.1146067Crossref PubMed Scopus (386) Google Scholar, Thermann and Hentze, 2007Thermann R. Hentze M.W. Nature. 2007; 447: 875-878Crossref PubMed Scopus (237) Google Scholar, Wakiyama et al., 2007Wakiyama M. Takimoto K. Ohara O. Yokoyama S. Genes Dev. 2007; 21: 1857-1862Crossref PubMed Scopus (230) Google Scholar). These new findings indicate that miRNAs inhibit translation at early steps of initiation. MicroRNAs (miRNAs) control gene expression by regulating mRNA stability and translation. Using cell-free in vitro systems, several labs have recently reported insights into the molecular mechanisms underlying miRNA-guided translational repression (Kiriakidou et al., 2007Kiriakidou M. Tan G.S. Lamprinaki S. De Planell-Saguer M. Nelson P.T. Mourelatos Z. Cell. 2007; 129: 1141-1151Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, Mathonnet et al., 2007Mathonnet G. Fabian M.R. Svitkin Y.V. Parsyan A. Huck L. Murata T. Biffo S. Merrick W.C. Darzynkiewicz E. Pillai R.S. et al.Science. 2007; (Published online July 26, 2007)https://doi.org/10.1126/science.1146067Crossref PubMed Scopus (386) Google Scholar, Thermann and Hentze, 2007Thermann R. Hentze M.W. Nature. 2007; 447: 875-878Crossref PubMed Scopus (237) Google Scholar, Wakiyama et al., 2007Wakiyama M. Takimoto K. Ohara O. Yokoyama S. Genes Dev. 2007; 21: 1857-1862Crossref PubMed Scopus (230) Google Scholar). These new findings indicate that miRNAs inhibit translation at early steps of initiation. MicroRNAs (miRNAs) constitute a class of small noncoding RNAs that have central roles in gene silencing and function as part of large gene regulatory networks. Although genes encoding miRNAs have been found in organisms as diverse as plants, animals, and viruses, the cellular functions of most of them are unknown. After transcription by RNA polymerases II or III, primary miRNA transcripts are processed into stem-loop-structured miRNA precursors that are further processed by the RNase III enzyme Dicer to double-stranded miRNA/miRNA∗ intermediates that are ∼21 nucleotides long (Filipowicz et al., 2005Filipowicz W. Jaskiewicz L. Kolb F.A. Pillai R.S. Curr. Opin. Struct. Biol. 2005; 15: 331-341Crossref PubMed Scopus (413) Google Scholar, Zamore and Haley, 2005Zamore P.D. Haley B. Science. 2005; 309: 1519-1524Crossref PubMed Scopus (1099) Google Scholar). Downstream unwinding and processing activities preferentially select one strand to become the mature miRNA, whereas the miRNA∗ strand is rapidly degraded. MicroRNAs specifically interact with members of the Argonaute (Ago) protein family and are incorporated into large ribonucleoprotein effector complexes termed miRNPs (Parker and Barford, 2006Parker J.S. Barford D. Trends Biochem. Sci. 2006; 31: 622-630Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, Peters and Meister, 2007Peters L. Meister G. Mol. Cell. 2007; 26: 611-623Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar). In animals, miRNAs hybridize to partially complementary binding sites typically located in the 3′ untranslated region (UTR) of target mRNAs and repress their expression. Efficient repression is either achieved by interfering with translation or by guiding processes for mRNA degradation that are initiated by deadenylation and decapping of the mRNA (Pillai et al., 2007Pillai R.S. Bhattacharyya S.N. Filipowicz W. Trends Cell Biol. 2007; 17: 118-126Abstract Full Text Full Text PDF PubMed Scopus (871) Google Scholar). In plants and in rare cases also in animals, mRNAs contain highly complementary miRNA-binding sites and therefore miRNAs guide the sequence-specific cleavage of the mRNA in a process similar to RNA interference (RNAi) (Peters and Meister, 2007Peters L. Meister G. Mol. Cell. 2007; 26: 611-623Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar). Due to extensive efforts in recent years, the mechanistic details of sequence-specific RNA cleavage in RNAi are well understood. However, the molecular mechanisms underlying miRNA-guided translational repression and mRNA destabilization are only poorly characterized. In recent work, four different groups have gained new insights into miRNA function by using cell-free in vitro systems (Mathonnet et al., 2007Mathonnet G. Fabian M.R. Svitkin Y.V. Parsyan A. Huck L. Murata T. Biffo S. Merrick W.C. Darzynkiewicz E. Pillai R.S. et al.Science. 2007; (Published online July 26, 2007)https://doi.org/10.1126/science.1146067Crossref PubMed Scopus (386) Google Scholar, Thermann and Hentze, 2007Thermann R. Hentze M.W. Nature. 2007; 447: 875-878Crossref PubMed Scopus (237) Google Scholar, Wakiyama et al., 2007Wakiyama M. Takimoto K. Ohara O. Yokoyama S. Genes Dev. 2007; 21: 1857-1862Crossref PubMed Scopus (230) Google Scholar, Wang et al., 2006Wang B. Love T.M. Call M.E. Doench J.G. Novina C.D. Mol. Cell. 2006; 22: 553-560Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). These findings mark an important turning point for the miRNA field, as these cell-free in vitro assays allow for a detailed biochemical dissection of the mechanisms underlying miRNA-guided gene silencing. Although a steady stream of miRNA targets are being reported, the majority of mRNAs regulated by miRNAs remain unknown. Therefore, studies on the mechanism of miRNA-guided translational repression have been carried out using artificial luciferase constructs with imperfect miRNA-binding sites. Transfection of such reporters into cells demonstrated that efficient miRNA-guided translational inhibition requires a functional 7-methyl-guanine (m7G) cap (Humphreys et al., 2005Humphreys D.T. Westman B.J. Martin D.I. Preiss T. Proc. Natl. Acad. Sci. USA. 2005; 102: 16961-16966Crossref PubMed Scopus (465) Google Scholar, Pillai et al., 2005Pillai R.S. Bhattacharyya S.N. Artus C.G. Zoller T. Cougot N. Basyuk E. Bertrand E. Filipowicz W. Science. 2005; 309: 1573-1576Crossref PubMed Scopus (1083) Google Scholar). However, one study demonstrated that the presence of a poly(A) tail is required (Humphreys et al., 2005Humphreys D.T. Westman B.J. Martin D.I. Preiss T. Proc. Natl. Acad. Sci. USA. 2005; 102: 16961-16966Crossref PubMed Scopus (465) Google Scholar), whereas another paper reported that miRNA-guided translational repression is independent of a poly(A) tail (Pillai et al., 2005Pillai R.S. Bhattacharyya S.N. Artus C.G. Zoller T. Cougot N. Basyuk E. Bertrand E. Filipowicz W. Science. 2005; 309: 1573-1576Crossref PubMed Scopus (1083) Google Scholar). In order to investigate miRNA function in translation using biochemistry, Wang et al., 2006Wang B. Love T.M. Call M.E. Doench J.G. Novina C.D. Mol. Cell. 2006; 22: 553-560Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar utilized a rabbit reticulocyte lysate system and showed that miRNA-guided translational inhibition requires a functional m7G-cap as well as a poly(A) tail (Wang et al., 2006Wang B. Love T.M. Call M.E. Doench J.G. Novina C.D. Mol. Cell. 2006; 22: 553-560Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). Now Wakiyama et al., 2007Wakiyama M. Takimoto K. Ohara O. Yokoyama S. Genes Dev. 2007; 21: 1857-1862Crossref PubMed Scopus (230) Google Scholar have established a cell-free extract system derived from human embryonic kidney (HEK) 293 cells that overexpress known RNAi components, such as Ago2 and GW182. Human GW182, which is also known as TNRC6A, belongs to a family of tri-nucleotide repeat-containing proteins. TNRC6A and TNRC6B have been shown to be essential for miRNA-guided gene silencing in various organisms. Using a biotinylated capped and polyadenylated reporter mRNA containing six artificial binding sites in its 3′UTR for the miRNA let-7, they show that FLAG-tagged Ago2 and FLAG-tagged GW182 are specifically recruited to the reporter mRNA. In this cell-free system, efficient repression of translation requires an m7G-cap as well as a poly(A) tail. Interestingly, it was found in the HEK293 cell lysates that the mRNA containing let-7-binding sites in its 3′UTR was efficiently deadenylated and that this was dependent on let-7. Deadenylation was independent of translation, as addition of cycloheximide, which blocks translation elongation, had no effect on deadenylation. However, translation efficiency was strongly correlated to deadenylation of the reporter mRNA (Wakiyama et al., 2007Wakiyama M. Takimoto K. Ohara O. Yokoyama S. Genes Dev. 2007; 21: 1857-1862Crossref PubMed Scopus (230) Google Scholar). Notably, Wakiyama et al. coexpressed GW182, a protein known to recruit deadenylation enzymes to mRNAs (Behm-Ansmant et al., 2006Behm-Ansmant I. Rehwinkel J. Doerks T. Stark A. Bork P. Izaurralde E. Genes Dev. 2006; 20: 1885-1898Crossref PubMed Scopus (688) Google Scholar). miRNA function might therefore be biased towards deadenylation in this system, and it would be interesting to see if similar observations could be made in a wild-type HEK293 lysate. The recent study by Sonenberg and coworkers utilized unmodified mammalian cell extracts (Mathonnet et al., 2007Mathonnet G. Fabian M.R. Svitkin Y.V. Parsyan A. Huck L. Murata T. Biffo S. Merrick W.C. Darzynkiewicz E. Pillai R.S. et al.Science. 2007; (Published online July 26, 2007)https://doi.org/10.1126/science.1146067Crossref PubMed Scopus (386) Google Scholar). Mathonnet et al., 2007Mathonnet G. Fabian M.R. Svitkin Y.V. Parsyan A. Huck L. Murata T. Biffo S. Merrick W.C. Darzynkiewicz E. Pillai R.S. et al.Science. 2007; (Published online July 26, 2007)https://doi.org/10.1126/science.1146067Crossref PubMed Scopus (386) Google Scholar used extracts from mouse Krebs-2 ascites cells and luciferase constructs carrying six artificial let-7-binding sites to show that translation of the reporter is inhibited in a concentration-dependent manner reflecting the levels of endogenous let-7. By incubating radiolabeled mRNAs in cell lysates, the authors demonstrate that mRNA levels of the let-7 reporter and a control reporter behave similarly, at least in the first 40 min of the reaction. Therefore, differences in activity are due to effects on translation. Interestingly, at later time points mRNA levels decrease and this effect is dependent on let-7, suggesting that inhibition of translation is an early event in miRNA-guided gene silencing and is at least to some extent followed by mRNA degradation. Sonenberg and coworkers then took advantage of their cell-free system to analyze the step of translation that is inhibited by let-7. Using glycerol gradients, they found that formation of the 80S ribosome complex is significantly reduced when the let-7 reporter was used, demonstrating that let-7 inhibits ribosome recruitment to the mRNA. Moreover, addition of recombinant eIF4F (the cap-binding complex) interfered with let-7-guided inhibition, indicating that miRNAs inhibit translational initiation by targeting the mRNA cap structure. The data obtained from the in vitro assays by Mathonnet et al., 2007Mathonnet G. Fabian M.R. Svitkin Y.V. Parsyan A. Huck L. Murata T. Biffo S. Merrick W.C. Darzynkiewicz E. Pillai R.S. et al.Science. 2007; (Published online July 26, 2007)https://doi.org/10.1126/science.1146067Crossref PubMed Scopus (386) Google Scholar and Wakiyama et al., 2007Wakiyama M. Takimoto K. Ohara O. Yokoyama S. Genes Dev. 2007; 21: 1857-1862Crossref PubMed Scopus (230) Google Scholar raised the question of how miRNPs that are bound to the 3′UTR of a target mRNA interfere with translational initiation. By analyzing the amino acid sequence of human Ago proteins in detail, Mourelatos and coworkers recently reported in Cell significant progress toward answering this question (Kiriakidou et al., 2007Kiriakidou M. Tan G.S. Lamprinaki S. De Planell-Saguer M. Nelson P.T. Mourelatos Z. Cell. 2007; 129: 1141-1151Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). Ago proteins contain a highly conserved motif that shows similarity to the m7G-cap-binding motif of eIF4E. Two amino acids with aromatic side chains that specifically bind the m7G-cap are a characteristic feature of this motif. Indeed, tagged human Ago2 isolated from HEK293 cells efficiently interacted with m7G-sepharose, whereas an Ago2 variant in which the two critical phenylalanines have been mutated did not. Interestingly, the Ago2 mutant retained the ability to cleave target mRNAs, indicating that the mutations did not alter Ago2 folding. Ago proteins inhibit translation when artificially tethered to the 3′UTR of mRNAs (Pillai et al., 2004Pillai R.S. Artus C.G. Filipowicz W. RNA. 2004; 10: 1518-1525Crossref PubMed Scopus (284) Google Scholar). However, the Ago2 variant with mutations in the cap-binding motif no longer inhibited translation, indicating that the interaction of Ago proteins and the mRNA cap structure are required for translational repression. Based on these observations a model for miRNA-guided interference of translational initiation can be proposed (Figure 1). In this model Ago proteins compete with eIF4E for cap binding. Once an Ago protein is bound, the cap is no longer accessible for eIF4E and translational initiation is repressed. Further mechanistic insights into miRNA-guided translational repression are provided by Thermann and Hentze, 2007Thermann R. Hentze M.W. Nature. 2007; 447: 875-878Crossref PubMed Scopus (237) Google Scholar. They introduced six miR-2-binding sites of the reaper mRNA into the 3′UTR of a firefly luciferase reporter and incubated it with Drosophila embryo lysates. Similar to the in vitro systems described above, translation of the miR-2 reporter was inhibited by endogenous miR-2, and this inhibition required an intact cap structure of the mRNA. 80S complex formation on the reporter mRNA containing the reaper miR-2-binding sites was inhibited by miR-2 as observed in mouse cell lysates. Interestingly, Thermann and Hentze realized that the miR-2 reporter construct shifts toward heavier fractions in sucrose gradients when repressed by miR-2. Moreover, this shift occurred in the presence of cycloheximide, which blocks translational elongation and therefore the establishment of polysomes. Due to their comigration with polysomes in density gradients the authors referred to these structures as “pseudo-polysomes.” A closer investigation revealed that miR-2 is found in pseudo-polysomes and that these structures constitute large EDTA-sensitive mRNA-protein (mRNP) assemblies. What are pseudo-polysomes and how do they contribute to miRNA-guided gene silencing? Pseudo-polysomes appear to be large protein-mRNA aggregates, and therefore it is tempting to speculate that such assemblies might resemble cytoplasmic processing bodies (P bodies). P bodies are highly dynamic structures that can adopt different dimensions and have been implicated in miRNA function (Eulalio et al., 2007Eulalio A. Behm-Ansmant I. Izaurralde E. Nat. Rev. Mol. Cell Biol. 2007; 8: 9-22Crossref PubMed Scopus (716) Google Scholar, Franks and Lykke-Andersen, 2007Franks T.M. Lykke-Andersen J. Genes Dev. 2007; 21: 719-735Crossref PubMed Scopus (185) Google Scholar). EDTA sensitivity might indicate that pseudo-polysomes are reversible structures, which has been shown for P bodies as well, and suggests that repressed mRNPs that aggregate into pseudo-polysomes could disaggregate and return to active translation. This would explain recent findings that mRNAs targeted by miRNAs localize to P bodies and that miRNA-guided translational repression is reversible (Bhattacharyya et al., 2006Bhattacharyya S.N. Habermacher R. Martine U. Closs E.I. Filipowicz W. Cell. 2006; 125: 1111-1124Abstract Full Text Full Text PDF PubMed Scopus (1018) Google Scholar). Notably, pseudo-polysomes have only been observed in the system that uses Drosophila embryo lysates, but not in extracts of mouse Krebs-2 ascites cells. It is therefore unclear whether this mechanism of miRNA-guided pseudo-polysome formation is a general phenomenon. One surprising aspect of the work by Thermann and Hentze, 2007Thermann R. Hentze M.W. Nature. 2007; 447: 875-878Crossref PubMed Scopus (237) Google Scholar is that an intact m7G-cap structure is not essential for the formation of pseudo-polysomes, as pseudo-polysomes also form on mRNAs containing artificial, nonfunctional cap structures (A-cap, ApppN) that do not support translational initiation. However, miR-2-guided repression of 80S complex assembly on the luciferase reporter mRNA strictly requires an m7G-cap. These findings suggest that the formation of pseudo-polysomes and presumably also P bodies does not require active translational repression by miRNAs. miRNA binding to the 3′UTR and inhibition of translation initiation seem to be enough to form large pseudo-polysomes, even when the inhibition is independent of the miRNA pathway. The cell-free translation systems that have been recently reported clearly put forward a model in which miRNAs interfere with translational initiation. However, initial studies in C. elegans and more recent studies in mammals have shown that miRNAs cosediment with polyribosomes, which has led to the suggestion that miRNAs are involved in regulating translational elongation (Maroney et al., 2006Maroney P.A. Yu Y. Fisher J. Nilsen T.W. Nat. Struct. Mol. Biol. 2006; 13: 1102-1107Crossref PubMed Scopus (243) Google Scholar, Nottrott et al., 2006Nottrott S. Simard M.J. Richter J.D. Nat. Struct. Mol. Biol. 2006; 13: 1108-1114Crossref PubMed Scopus (298) Google Scholar, Olsen and Ambros, 1999Olsen P.H. Ambros V. Dev. Biol. 1999; 216: 671-680Crossref PubMed Scopus (919) Google Scholar, Petersen et al., 2006Petersen C.P. Bordeleau M.E. Pelletier J. Sharp P.A. Mol. Cell. 2006; 21: 533-542Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar, Seggerson et al., 2002Seggerson K. Tang L. Moss E.G. Dev. Biol. 2002; 243: 215-225Crossref PubMed Scopus (293) Google Scholar). In some of these studies, cosedimentation with polysomes was abolished after puromycin treatment, which disassembles polysomes. It has also been shown that nascent polypeptides are rapidly degraded when mRNAs are under miRNA regulation (Nottrott et al., 2006Nottrott S. Simard M.J. Richter J.D. Nat. Struct. Mol. Biol. 2006; 13: 1108-1114Crossref PubMed Scopus (298) Google Scholar). Moreover, it has also been observed that ribosomes drop off mRNAs when miRNAs bind to the 3′UTR, which has led to a ribosome drop-off model of miRNA function (Petersen et al., 2006Petersen C.P. Bordeleau M.E. Pelletier J. Sharp P.A. Mol. Cell. 2006; 21: 533-542Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar). How could such discrepancies related to the function of miRNAs be explained? Although a role for miRNAs in initiation of translation is now well documented, it cannot be excluded that miRNAs also function during other steps of translation. It is reasonable to propose that miRNAs have distinct functions on different mRNAs or during different cellular or developmental stages. Notably, most studies on miRNA function have been performed with reporters containing artificial or isolated miRNA-binding sites. Such reporters are very helpful in elucidating the basic mechanistic steps of this process; however, these functions may differ in the context of large native 3′UTRs where location of the binding sites as well as the interplay with other regulatory proteins is important. In some studies, however, it is also possible that the comigration of miRNAs or protein components of the miRNA pathway with polysomes has been misinterpreted as polysome association. In light of the recent study by Thermann and Hentze, 2007Thermann R. Hentze M.W. Nature. 2007; 447: 875-878Crossref PubMed Scopus (237) Google Scholar, such structures might be large miRNP aggregates or pseudo-polysomes. Although still controversial, it is becoming increasingly apparent that at least one function of miRNAs is the inhibition of translational initiation. The reported data from the cell-free translation systems raise many new questions. How are pseudo-polysomes formed and how is this process regulated? How do such structures disaggregate to allow for re-entry into active translation? What are the protein components of pseudo-polysomes and how are they related to P bodies? The use of these new biochemical systems in conjunction with proteomic approaches and other cell biological studies will help to further elucidate miRNA function. I thank A. Frohn, C. Ender, L. Weinmann, and M. Kiebler for helpful discussions. Our research is supported by the Max-Planck-Society, the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, and the European Union." @default.
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• W1982131024 title "miRNAs Get an Early Start on Translational Silencing" @default.
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