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From RNAi to epigenomes: how RNA rules the world.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Westhof, Eric Filipowicz, W. |
| Copyright Year | 2005 |
| Abstract | Last October, the Boehringer Ingelheim Fonds sponsored and organized an international conference on RNA Silencing that was chaired by Thomas Tuschl from Rockefeller University, New York, and Thomas Jenuwein from the Institute of Molecular Pathology, Vienna. During two days, twenty-five speakers presented their results to an attentive and very reactive audience. It cannot have escaped the attention of any scientist interested in biology that tiny RNA molecules are transforming our thinking on genetic regulatory processes. It is now realized that post-transcriptional gene silencing (PGTS) or cosuppression in plants, quelling in fungi and RNA interference in animals all share common processing mechanisms. RNA interference (RNAi) describes the process by which doublestranded RNA (dsRNA) introduced into cells leads to the degradation of the messenger RNAs, which contain regions homologous to the triggering dsRNA. In 1998, Fire, Mello and co-workers demonstrated that dsRNA promotes the degradation in a sequence-specific manner of endogenous RNAs in a worm. It was already known by then that RNAi/PTGS in plants and worms was systemic and heritable. These two properties require catalytic and amplification mechanisms, which have been partly biochemically characterized. Recent experiments also provide some hints as to how RNAi can spread throughout the organism. Starting, in 1999, with the establishment of a cell-free Drosophila system able to recapitulate many of the features of RNAi, Tuschl and collaborators could demonstrate that RNAi can be mediated by sequence-specific processes in soluble reactions. By using this system, it could be further shown that, during RNAi, both strands are processed to 21–23 nt RNAs in an ATP-dependent manner. Strikingly, small RNAs of similar size have been previously identified as molecules that accompany RNA silencing in plants. Simultaneously, a silencing complex containing small RNAs was beginnig to be characterized. Processing of dsRNA to small RNAs does not require the target mRNA; however, the cleavage of the mRNA is guided by the pairing to the complementary region. The demonstration that duplexes of 21-nt RNAs with 2-nt 3’ overhangs (small interfering RNAs, siRNAs) are the sequence-specific mediators of RNAi constituted a most crucial discovery in an expanding new field of RNA research. Indeed, soon afterwards, it was demonstrated that siRNAs can be used for the silencing of gene expression in mammalian cells without activation of the mammalian interferon system, thereby providing a new tool for genome-wide analysis of human gene function. 14] For a recent debate about some siRNAs being nevertheless able to induce the interferon response, see the article by Jackson and Linsley. A little bit later, formation of both siRNAs and the genome-encoded ~21-nt RNA regulators, originally known as small temporal RNAs but soon rebaptized microRNAs (miRNAs), was shown to require DICER, a multidomain nuclease related to RNase III enzymes that have specificity for dsRNA. 17] Genetic, biochemical and bioinformatic approaches identified large numbers of miRNAs and their genes in both invertebrates and vertebrates, thus demonstrating that these tiny RNA regulators are not the oddity of the nematode worm Caenorhabditis elegans, where they were originally discovered in 1993. siRNAs in plants and animals associate with a set of specific proteins to form the effector complex, called RISC (for RNA-Induced Silencing Complex), which mediates the mRNA cleavage in the middle of the sequence complementary to siRNA (Scheme 1). In contrast, most miRNAs in animals form imperfect duplexes with sequences in the 3’-untranslated region (3’-UTR) of mRNAs and block protein synthesis by an unknown mechanism (Scheme 2). In plants, however, miRNAs generally base-pair quite precisely with their targets and guide, as do siRNAs, the mRNA cleavage. b] miRNAs form part of RISC-like ribonucleoprotein particles, miRNPs. b] The protein composition of RISC and miRNP particles partly overlaps (for example, both types of complexes contain proteins of the Argonaute family) ; this is consistent with miRNAs’ being able to act as siRNAs under some circumstances, and vice versa. 19, 20] These RNA-guided silencing mechanisms opened a whole new field not only in RNA research but also for our un- |
| Starting Page | 1 |
| Ending Page | 6 |
| Page Count | 6 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www-ibmc.u-strasbg.fr/arn/Westhof/publ_West/bib2005/r2005_EWesthof_Chembiochem.pdf |
| Alternate Webpage(s) | http://www-ibmc.u-strasbg.fr/upr9002/westhof/PDF/r2005_EWesthof_Chembiochem.pdf |
| PubMed reference number | 15651038v1 |
| Volume Number | 6 |
| Issue Number | 2 |
| Journal | Chembiochem : a European journal of chemical biology |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Adenosine Triphosphate Argonaute Proteins Databases, Genetic Fungi Gene Expression Invertebrates Mammals MicroRNAs Phylum Nematoda Protein Biosynthesis RNA Interference RNA, Double-Stranded RNA-Induced Silencing Complex Ribonuclease III Ribonucleoproteins Rule (guideline) Terminator Regions, Genetic Transcription, Genetic Twenty Five Vertebrates negative regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay nuclease |
| Content Type | Text |
| Resource Type | Article |
