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PubMed2003

Double RNA interference of DNMT3b and DNMT1 enhances DNA demethylation and gene reactivation.

Small interfering RNAs (siRNAs) are newly identified molecules shown to silence genes via targeted mRNA degradation. In this study, we used specific siRNAs as a tool to probe the relationship between two DNA methyltransferase genes, DNMT3b and DNMT1, in the maintenance of DNA methylation patterns in the genome. Levels of DNMT3b or DNMT1 mRNAs and proteins were markedly decreased (up to 80%) on transfecting these siRNAs into the ovarian cancer cell line CP70. The resulting RNA interference showed differential effects on DNA demethylation and gene reactivation in the treated cells. The DNMT1 siRNA treatment led to a partial removal of DNA methylation from three inactive promoter CpG islands, TWIST, RASSF1A, and HIN-1, and restored the expression of these genes. This epigenetic alteration appeared less effective in cells transfected with DNMT3b siRNA. However, the combined treatment of DNMT3b and DNMT1 siRNAs greatly enhanced this demethylation effect, producing 7-15-fold increases in their expression. We also used a microarray approach to examine this RNA interference on 8640 CpG island loci in CP70 cells. The combined siRNA treatment had a greater demethylation effect on 241 methylated loci and selected repetitive sequences than that of the single treatment. Our data thus suggest that whereas DNMT1 plays a key role in methylation maintenance, DNMT3b may act as an accessory to support the function in CP70 cells. This study also shows that siRNA is a powerful tool for interrogating the mechanisms of DNA methylation in normal and pathological genomes.

Cell Division↗

PubMedDate not supplied

Inhibition of HPV 16 E6 oncogene expression by RNA interference in vitro and in vivo.

Substantial studies have demonstrated that the initiation and progression of cervical cancer were closely associated with human papillomavirus (HPV) E6 and E7 oncogenes. The therapeutic strategy with ribozyme or antisense oligonucleotides to inhibit the expression of HPV E6 or E7 oncogenes showed effect to some degree, but problems such as low efficiency, short-period maintenance, and high cost still remain. The aim of this study was to investigate in vitro and in vivo the effect of HPV 16 E6 small interfering RNA (HPV 16 E6 siRNA) on cervical cancer cell line CaSki cells. The specific siRNA of HPV 16 E6 was synthesized and transfected into CaSki cells by liposome. The number of apoptotic cells, HPV 16 E6 messenger RNA (mRNA) level, and E6 protein expression were measured before and after the transfection by flow cytometry, reverse transcriptase-polymerase chain reaction, and Western blot, respectively. Cervical cancer in nude mice was established, and siRNA was injected directly into the nude mice peritoneal cavity or subcutaneous tumor. The efficiency of siRNA was evaluated by tumor volume change, HPV 16 E6 protein expression, and apoptosis of tumor cells. Apoptosis rate of CaSki cells at days 1, 2, 5, and 9 after siRNA transfection were 7.7%, 11.8%, 37.4%, and 12.6%, respectively. The mRNA level of HPV 16 E6 at the same time points were reduced by 77%, 83%, 59%, and 41%, respectively. But the mRNA level of beta-actin, as an internal control, showed no significant change. The inhibition rates of E6 protein synthesis at days 1, 2, 5, and 9 after the transfection were 79.7%, 80.4%, 71.3%, and 57.4%, respectively, whereas the protein levels of Lamin A/C, as internal control, had no change. In vivo, E6 siRNA administration groups showed a dramatic effect in inhibiting tumor growth, suppressing expression of E6 protein, and inducing tumor necrosis and apoptosis as compared with the control group. Direct injection of siRNA into subcutaneous tumor resulted in tumor suppression effect similar to that via the peritoneal cavity, and with additional injection better results could be achieved in cervical cancer CaSki cells. RNA interference exists, and the interference to HPV 16 E6 is specific and highly efficient both in vitro and in vivo.

Animals↗

PubMed2006

RNA interference analysis of Legionella in Drosophila cells: exploitation of early secretory apparatus dynamics.

Legionella pneumophila translocates multiple bacterial effector proteins into host cells to direct formation of a replication vacuole for the bacterium. The emerging consensus is that formation of this compartment involves recruitment of membrane material that traffics between the endoplasmic reticulum (ER) and Golgi. To investigate this model, a targeted approach was used to knock down expression of proteins involved in membrane trafficking, using RNA interference in Drosophila cells. Surprisingly, few single knockdowns of ER-Golgi transport proteins decreased L. pneumophila replication. By analyzing double-stranded RNAs in pairs, combinations were identified that together caused defects in intracellular replication, consistent with the model that membrane traffic funnels into the replication vacuole from multiple sources. In particular, simultaneous depletion of the intermediate compartment and Golgi-tethering factor transport protein particle together with the ER SNARE protein Sec22 reduced replication efficiency, indicating that introduction of lesions at distinct sites in the secretory system reduces replication efficiency. In contrast to knockdowns in secretory traffic, which required multiple simultaneous hits, knockdown of single cytosolic components of ER-associated degradation, including Cdc48/p97 and associated cofactors, was sufficient to inhibit intracellular replication. The requirement for the Cdc48/p97 complex was conserved in mammalian cells, in which replication vacuoles showed intense recruitment of ubiquitinated proteins, the preferred substrates of Cdc48/p97. This complex promoted dislocation of both ubiquitinated proteins and bacterial effectors from the replication vacuole, consistent with the model that maintenance of high-level replication requires surveillance of the vacuole surface. This work demonstrates that L. pneumophila has the ability to gain access to multiple sites in the secretory system and provides the first evidence for a role of the Cdc48/p97 complex in promoting intracellular replication of pathogens and maintenance of replication vacuoles.

Adenosine Triphosphatases↗

PubMed2006

Cyclooxygenase-2 knockdown by RNA interference in colon cancer.

Overexpression of cyclooxygenase-2 (COX-2) is observed early in colon cancer. Treatments with COX-2-specific NSAIDs have been shown to reduce polyp size and polyp number in FAP patients with a predisposition to colorectal adenoma and cancer. However, the use of COX-2-specific NSAIDs in colon cancer patients has recently revealed increased cardiovascular risks. These harmful side effects may be the result of COX-dependent and/or COX-independent mechanisms. RNA interference (RNAi) is a method of post-transcriptional gene silencing intrinsic to cells. This study employed RNAi to specifically knockdown endogenous COX-2 expression in the HT-29 colon cancer cell line, and to observe the apoptotic response as well as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression levels. Following treatment with a COX-2 siRNA, we demonstrated a significant knockdown at the protein level of 57% as compared to a non-silencing siRNA control. Protein results were corroborated by concurrent decrease in COX-2 mRNA levels following the same treatment regimen. Despite previous studies using NSAID treatment to implicate COX-2 involvement in apoptosis, we did not observe any alteration in Bcl-2 expression and Caspase-3 activation following COX-2 knockdown in these cells. 15-PGDH, a physiological antagonist of COX-2 in its catabolism of PGE2, showed a modest but significant induction in response to COX-2 knockdown. The precise role of COX-2 in apoptosis and PGE2 regulation remains unclear; however, having shown that down-regulation of endogenous levels of COX-2 can be achieved in colon cancer by RNAi, this strategy should prove to be a valuable tool in revealing the specific function of COX-2 in tumourigenesis.

Colonic Neoplasms↗

PubMed2006

RNA interference as a key to knockdown overexpressed cyclooxygenase-2 gene in tumour cells.

Silencing those genes that are overexpressed in cancer and contribute to the survival and progression of tumour cells is the aim of several researches. Cyclooxygenase-2 (COX-2) is one of the most intensively studied genes since it is overexpressed in most tumours, mainly in colon cancer. The use of specific COX-2 inhibitors to treat colon cancer has generated great enthusiasm. Yet, the side effects of some inhibitors emerging during long-term treatment have caused much concern. Genes silencing by RNA interference (RNAi) has led to new directions in the field of experimental oncology. In this study, we detected sequences directed against COX-2 mRNA, that potently downregulate COX-2 gene expression and inhibit phorbol 12-myristate 13-acetate-induced angiogenesis in vitro in a specific, nontoxic manner. Moreover, we found that the insertion of a specific cassette carrying anti-COX-2 short hairpin RNA sequence into a viral vector (pSUPER.retro) greatly increased silencing potency in a colon cancer cell line (HT29) without activating any interferon response. Phenotypically, COX-2 deficient HT29 cells showed a significant impairment of their in vitro malignant behaviour. Thus, the retroviral approach enhancing COX-2 knockdown, mediated by RNAi, proved to be an useful tool to better understand the role of COX-2 in colon cancer. Furthermore, the higher infection efficiency we observed in tumour cells, if compared to normal endothelial cells, may disclose the possibility to specifically treat tumour cells without impairing endothelial COX-2 activity.

Carcinogens↗

PubMed2003

RNA interference silences Microplitis demolitor bracovirus genes and implicates glc1.8 in disruption of adhesion in infected host cells.

The family Polydnaviridae consists of ds-DNA viruses that are symbiotically associated with certain parasitoid wasps. PDVs are transmitted vertically but also are injected by wasps into hosts where they cause several physiological alterations including immunosuppression. The PDV genes responsible for mediating immunosuppression and other host alterations remain poorly characterized in large measure because viral mutants cannot be produced to study gene function. Here we report the use of RNA interference (RNAi) to specifically silence the glc1.8 and egf1.0 genes from Microplitis demolitor bracovirus (MdBV) in High Five cells derived from the lepidopteran Trichoplusia ni. Dose-response studies indicated that MdBV infects High Five cells and blocks the ability of these cells to adhere to culture plates. This response was very similar to what occurs in two classes of hemocytes, granular cells, and plasmatocytes, after infection by MdBV. Screening of monoclonal antibody (mAb) markers that distinguish different classes of lepidopteran hemocytes indicated that High Five cells cross-react with three mAbs that recognize granular cells from T. ni. Double-stranded RNA (dsRNA) complementary to glc1.8 specifically silenced glc1.8 expression and rescued the adhesive phenotype of High Five cells. Reciprocally, dsRNA complementary to egf1.0 silenced egf1.0 expression but had no effect on adhesion. The simplicity and potency of RNAi could be extremely useful for analysis of other PDV genes.

Animals↗

PubMed2005

RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance.

Integrin-linked kinase (ILK) facilitates signal transduction between extracellular events and important intracellular survival pathways involving protein kinase B/Akt. We examined the role of ILK in determining pancreatic adenocarcinoma cellular chemoresistance to the nucleoside analogue gemcitabine. Cellular ILK expression was quantified by Western blot analysis. We examined the effects of overexpression of active ILK and of ILK knockdown induced by RNA interference on gemcitabine chemoresistance. We also examined the effects of modulating ILK expression on gemcitabine-induced caspase 3-mediated apoptosis, phosphorylation status of Akt (Ser473) and glycogen synthase kinase. Overexpression of ILK increased cellular gemcitabine chemoresistance, whereas ILK knockdown induced chemosensitization via increased caspase 3-mediated apoptosis. ILK knockdown attenuated Akt Ser473 and glycogen synthase kinase phosphorylation, whereas overexpression of constitutively active myristoylated Akt was sufficient to induce significant recovery in gemcitabine chemoresistance in the presence of ILK knockdown. Levels of ILK expression affect gemcitabine chemoresistance in pancreatic adenocarcinoma cells. This novel finding suggests that therapies directed against ILK and its downstream signaling targets may have the potential to enhance the efficacy of gemcitabine-based chemotherapy.

Adenocarcinoma↗

PubMed2004

Genome-wide expression profiling of RNA interference of hepatitis B virus gene expression and replication.

Small interfering RNA (siRNA) has been used repeatedly to down-regulate viral gene expression and inhibit viral replication in mammalian cells. In this study, we showed that siRNAs specific for two conserved regions within the hepatitis B S antigen (HBsAg) gene can inhibit antigen production in two human liver cell lines which constitutively produce and secrete HBsAg. The inhibitory effect was concentration dependent for both PLC/PRF/5 and 2.2.15 cells. Decreases in the corresponding viral transcript levels were observed. The inhibitory effect was observed within 24 h and was still evident 7 days after the initial treatment with siRNA. A significant reduction in virion production was also observed for the 2.2.15 cells. A critical consideration in this study was the specificity of the siRNA-mediated inhibition. To address this, we first examined the effects on cell growth and viability. These were not affected in either cell line. cDNA microarrays were also used to examine genome-wide changes in gene regulation. No significant off-target gene regulation was observed in either cell line. Our findings thus indicate that siRNA can specifically mediate the down-regulation of viral gene expression leading to a reduction in virion production.

Gene Expression Profiling↗

PubMed2004

[Reversal of multi-drug resistance in K562/A02 cells by small interference RNA of mdr1 gene].

OBJECTIVE: To investigate the effect of small interference RNA (siRNA) on mdr1 and P-glyco-protein (P-gp) expression of multi-drug resistance (MDR) human leukemia cell line K562/A02. METHODS: Three si RNAs (si-mdr1-1, si-mdr1-2, si-mdr1-3) which were specifically targeted mdr1 gene were synthesized and transfected into K562/A02 cells. Expression of mdr1 mRNA was assayed by RT-PCR. P-gp expression and intracellular daunorubicin (DNR) concentration were determined by flow cytometry. 50% inhibition concentration (IC(50)) of doxorubicin (ADM) on K562/A02 was determined by MTT method. RESULTS: Treatment of K562/A02 cell with the 3 kinds of siRNAs resulted in a reversal of MDR of a different extent. The third siRNA was more effective in the suppression of mdr1 with a significant reduction of (58.0 +/- 1.54)% of the mdr1 mRNA expression. Positive expression rate of p170 decreased from (76.0 +/- 1.0)% to (19.6 +/- 1.9)%, and the relative efficiency of K562/A02 to ADM was 70.4%. The intracellular accumulation of DNR increased after siRNA treatment. CONCLUSION: The siRNA could effectively restore the sensitivity of K562/A02 cells to conventional chemotherapeutic agents.

Base Sequence↗

PubMed2002

RNA interference in the pathogenic fungus Cryptococcus neoformans.

Cryptococcus neoformans is a pathogenic fungus responsible for serious disease in immunocompromised individuals. This organism has recently been developed as an experimental system, with initiation of a genome project among other molecular advances. However, investigations of Cryptococcus are hampered by the technical difficulty of specific gene replacements. RNA interference, a process in which the presence of double-stranded RNA homologous to a gene of interest results in specific degradation of the corresponding message, may help solve this problem. We have shown that expression of double-stranded RNA corresponding to portions of the cryptococcal CAP59 and ADE2 genes results in reduced mRNA levels for those genes, with phenotypic consequences similar to that of gene disruption. The two genes could also be subjected to simultaneous interference through expression of chimeric double-stranded RNA. Specific modulation of protein expression through introduction of double-stranded RNA thus operates in C. neoformans, which is the first demonstration of this technique in a fungal organism. Use of RNA interference in Cryptococcus should allow manipulation of mRNA levels for functional analysis of genes of interest and enable efficient exploration of genes discovered by genome sequencing.

Carboxy-Lyases↗

PubMedDate not supplied

Cytotoxic ribonucleases and RNA interference (RNAi).

Several cytotoxic ribonucleases (CRs), homologs of the pancreatic RNase A, have been isolated from amphibian oocytes or embryos. Of them, onconase (Onc), the CR that shows antitumor properties and is in phase III clinical trials, was the most extensively researched. Degradation of tRNA by Onc internalized into cells that leads to inhibition of protein synthesis is considered the mechanism of its cytotoxicity. Several findings, however, cannot be explained by nonspecific decline in protein synthesis alone and suggest additional or alternative mechanism(s). We postulate therefore that miRNAs and/or RNA interference (RNAi) may also be targets of CRs. The following arguments support this postulate: (A) miRNAs and siRNAs appear to be unprotected by proteins and therefore, as tRNA, accessible and degradable by CRs; (B) Onc has preferred cleavage sites on tRNAs: their cleavage may generate segments of dsRNA that interfere with translation. Analogous to Dicer, thus, small RNAs with interfering properties may be generated by CRs within the cell; (C) CRs are abundant in oocytes and during embryonic development; their role there is unknown. Since cells undergo perpetual differentiation during embryogenesis it is likely that the function of CRs is to provide additional level of regulation of gene expression via the mechanisms listed in (A) and/or (B).

Animals↗

PubMed2003

RNA interference as a metabolic engineering tool: potential for in vivo control of protein expression in an insect larval model.

Many ex vivo factors influence the yield of recombinant protein produced via AcMNPV (Autographa californica multiple nucleocapsid nuclear polyhedrosis virus) in Trichoplusia ni (T. ni) larvae. Among these are: the method of infection, the time of infection, the virus load, and the time of harvest. In vivo strategies, however, that attempt to manipulate host function in this and other expression systems have largely been ignored. In this work, RNA interference (RNAi) is shown as an effective metabolic engineering controller to downregulate targeted gene expression. Specifically, RNAi was made to virus-encoded gfp(uv) and was found to inhibit the production of GFPuv in larvae when injected within an 18-h window (before and after) of baculovirus infection. The level of inhibition was found to depend, both in duration and extent, on the concentration of injected RNAi. That relatively low levels of RNAi can inhibit protein synthesis driven by the strong polyhedrin (polh) promoter of AcMNPV, suggests that RNAi will find utility as an in vivo metabolic controller in metabolic engineering studies such as this one pertaining to protein expression.

Animals↗

PubMed2005

RNA interference (RNAi) for extracellular signal-regulated kinase 1 (ERK1) alone is sufficient to suppress cell viability in ovarian cancer cells.

While ovarian cancer is a leading cause of death in females today, the molecular, genetic, and environmental factors that initiate and support the progression of this disease are still only partially understood. The extracellular signal-regulated kinase (ERK) signaling pathway is a major contributor to cellular growth, differentiation and survival. Recently, we reported that this pathway is constitutively activated in ovarian cancer cells, and that by using RNA interference (RNAi) for ERK1 and ERK2, we were able to significantly suppress the number of viable tumor cells. In the present study, we have further investigated the mechanisms by which RNAi for the ERK kinases decreased viability in these cancer cells. It was determined that treatment of the cancer cells with small inhibitory RNAs (siRNAs) directed against ERK1 and ERK2 leads to the induction of apoptosis and necrosis by four hours following treatment. Additionally, we found that primary, nonmalignant ovarian cells do not respond similarly to ERK siRNA treatment and that these cells fail to die following treatment. Data presented show that ERK2 expression is more difficult to silence, depending upon cell type being examined and that silencing ERK1 expression alone is sufficient to significantly decrease tumor cell viability.

Apoptosis↗

PubMed2005

Nairovirus RNA sequences expressed by a Semliki Forest virus replicon induce RNA interference in tick cells.

We report the successful infection of the cell line ISE6 derived from Ixodes scapularis tick embryos by the tick-borne Hazara virus (HAZV), a nairovirus in the family Bunyaviridae. Using a recombinant Semliki Forest alphavirus replicon that replicates in these cells, we were able to inhibit replication of HAZV, and we showed that this blockage is mediated by the replication of the Semliki Forest alphavirus replicon; the vector containing the HAZV nucleoprotein gene in sense or antisense orientation efficiently inhibited HAZV replication. Moreover, expression of a distantly related nucleoprotein gene from Crimean-Congo hemorrhagic fever nairovirus failed to induce HAZV silencing, indicating that the inhibition is sequence specific. The resistance of these cells to replicate HAZV correlated with the detection of specific RNase activity and 21- to 24-nucleotide-long small interfering RNAs. Altogether, these results strongly suggest that pathogen-derived resistance can be established in the tick cells via a mechanism of RNA interference.

Animals↗

PubMed2006

Analysis of gene expression profile in colon cancer using the Cancer Genome Anatomy Project and RNA interference.

OBJECTIVE: To investigate the changes in the gene expression profile in colon cancer to further identify gene markers that may be useful in the management of this disease. METHODS: Data from serial analysis of gene expression (SAGE) collected by the Cancer Genome Anatomy Project (CGAP) were used to detect the difference in gene expression between normal tissue and colon cancer, and were further confirmed in a sample of 20 patients using RT-PCR. To identify the functions of differential genes in regulating the cell growth of colon cancer, RNA interference (RNAi) was used to block one of these genes in the colon cancer cell line HCT-116. RESULTS: Expression changes of greater than twofold in two SAGE libraries of colon cancer compared to two of normal tissue were observed for 216 tags of a total of 195,160 transcript tags (54 up-regulated genes and 136 down-regulated genes). Subsequent analysis of 17 genes by RT-PCR confirmed the reliability of this analysis. RNAi-mediated blockage of one of these genes, transforming growth factor (TGF)beta1, significantly reduced the growth of a colon cancer cell line. CONCLUSIONS: The combination of CGAP analysis and RNAi provides an excellent system to rapidly define the specific genes that are up-regulated in cancer to impact the growth of cancer cells. Further study on these differential overexpressed genes may provide gene markers for the detection and treatment of colon cancer.

Biomarkers, Tumor↗

PubMed2006

Reversal of MDR1/P-glycoprotein-mediated multidrug resistance by vector-based RNA interference in vitro and in vivo.

Overexpression of P-glycoprotein (P-gp) encoded by MDR1 gene in cancer cells results in multidrug resistance (MDR) to structurally and mechanistically different chemotherapeutic drugs, which is a major cause for cancer chemotherapy failures to cancer patients. Recently, there were several reports showing that expression of siRNAs targeting MDR1 gene is able to reverse the P-gp mediated MDR, however, the in vivo reversal effects for MDR have still not been identified. We developed a novel MDR reversal system using RNA interference technique in human epidermoid carcinoma KBv200 cells. The stably expressing MDR1 shRNA cells (KBv200/MDR1sh) were established with transfection of vector pEGFPC2-H1-MDR1shDNA containing MDR1-V siRNA expression cassette, and we found that more than 90% of MDR1 mRNA and P-gp were reduced. KBv200/MDR1sh cells simultaneously showed stably expressing EGFP and kept low MDR1 expression beyond ten passages. Compared KBv200/MDR1sh cells with KBv200 cells, resistance to vincristine and doxorubicin decreased from 62.4-fold to 10.5-fold and from 74.5-fold to 9.5-fold respectively, and intracellular doxorubicin accumulation enhanced from 0.30 +/- 0.08 nmoles/10(6) cells to 0.86 +/- 0.16 nmoles/10(6) cells, and the fluorescence intensity of intracellular Rhodamine 123 accumulation increased from 3.58 +/- 1.63/10(6) cells to 13.96 +/- 3.07/10(6) cells. In the nude mice xenografts, vincristine (0.2 mg/kg of body weight) inhibited the growth of KBv200/MDR1sh solid tumors by 42.0%, but the same dose of vincristine didn't inhibit the growth of KBv200 solid tumors significantly. These results suggest that administration of RNAi targeted MDR1 gene can effectively reverse MDR both in vitro and in vivo models.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Downregulation of eRF1 by RNA interference increases mis-acylated tRNA suppression efficiency in human cells.

The site-specific incorporation of non-natural amino acids into proteins by nonsense suppression has been widely used to investigate protein structure and function. Usually this technique exhibits low incorporation efficiencies of non-natural amino acids into proteins. We describe for the first time an approach for achieving an increased level of nonsense codon suppression with synthetic suppressor tRNAs in cultured human cells. We find that the intracellular concentration of the eukaryotic release factor 1 (eRF1) is a critical parameter influencing the efficiency of amino acid incorporation by nonsense suppression. Using RNA interference we were able to lower eRF1 gene expression significantly. We achieved a five times higher level of amino acid incorporation as compared with non-treated control cells, as demonstrated by enhanced green fluorescent protein (EGFP) fluorescence recovery after importing a mutated reporter mRNA together with an artificial amber suppressor tRNA.

Amino Acids↗

PubMedDate not supplied

[Regulation of the expression of repeated sequences and RNA interference].

Living organisms have to fight against the invasion of many parasites. Among them are viruses and transposable elements that are able to integrate in the genome of their host. After integration, they can replicate and propagate. The defence mechanisms against these invaders are still largely unknown but are widely studied in plants as well as in fungi and animals, particularly Caenorhabditis elegans and Drosophila melanogaster. The compilation of recent data allows us to draw a general scheme for these mechanisms. In particular, it seems that the propagation of viruses, transposable elements and repeated sequences is controlled by mechanisms repressing the expression of these sequences at both transcriptional and post-transcriptional levels. Post-transcriptional regulation of repeated sequences and transposable elements is related to RNA interference (RNAi), an evolutionary conserved silencing process induced by the presence of double-stranded RNAs (dsRNAs). Many genes and molecular intermediates have now been identified, revealing the different steps of the mechanism underlying this process. Finally, different results suggest that these post-transcriptional silencing processes are involved in the development of organisms. DICER is a nuclease responsible for the processing of dsRNA into short RNA molecules (siRNAs) considered as the interfering agent. siRNAs interact with the transcript of the targeted gene and this interaction induces degradation of the transcript. DICER is also involved in the processing of small temporal RNAs (stRNA) involved in the timing of development. stRNAs have the same structure as siRNAs. They regulate their target genes by interacting with elements present in their 3'UTR and blocking translation. RNAi appears to be an universal regulatory mechanism that was still unknown a few years ago. It is now largely used in large scale inactivation of genes to determine their function, and some recent studies indicate that it might be used in human therapy.

Animals↗