Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.26.3 (RNase III)
1,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MicroRNAs (miRNAs) are a class of small RNAs that have revealed a new level of gene regulation in the cell. After being processed by Drosha and Dicer RNase III endonucleases, mature miRNAs can inhibit the translation of mRNA by directing a RNA-induced silencing complex (RISC) to the target mRNA. miRNAs are making an impact in our understanding of cancer biology. Acting as either tumor suppressors or oncogenes, miRNAs regulate several genes known to play important roles in cancer. With the discovery of miRNAs comes the need for new techniques to study their activity. Bioinformatic tools can be used to predict mRNA targets of miRNA, but validation of miRNA regulation of predicted targets is imperative. miRNAs are differentially expressed in normal and tumor cells as well as between tumor subtypes. These differences may be useful as prognostic and predictive markers in cancer patients. The study of miRNAs holds much promise for improving diagnosis and treatment of cancer.
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PMID:MicroRNAs and cancer: past, present, and potential future. 1907 42

The generation of microRNAs is dependent on the RNase III enzyme Dicer, the levels of which vary in different normal cells and in disease states. We demonstrate that Dicer protein expression in JAR trophoblast cells, and several other cell types, was inhibited by multiple stresses including reactive oxygen species, phorbol esters and the Ras oncogene. Additionally, double-stranded RNA and Type I interferons repress Dicer protein in contrast to IFN-gamma which induces Dicer. The effects of stresses and interferons are primarily post-transcriptional. The findings suggest that Dicer is a stress response component and identifies interferons as potentially important regulators of Dicer expression.
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PMID:Dicer is regulated by cellular stresses and interferons. 1911 2

Ribonuclease III (RNase III) is a double-stranded (ds)-RNA-specific endonuclease that plays essential roles in the maturation and decay of coding and noncoding RNAs. Bacterial RNases III are structurally the simplest members of the RNase III family, which includes the eukaryotic orthologs Dicer and Drosha. High-resolution crystal structures of RNase III of the hyperthermophilic bacteria Aquifex aeolicus and Thermotoga maritima are available. A. aeolicus RNase III also has been cocrystallized with dsRNA or specific hairpin substrates. These structures have provided essential structural insight to the mechanism of dsRNA recognition and cleavage. However, comparatively little is known about the catalytic behaviors of A. aeolicus or T. maritima RNases III. This chapter provides protocols for the purification of A. aeolicus and T. maritima RNases III and also describes the preparation of artificial heterodimers of Escherichia coli RNase III, which are providing new insight on the subunit and domain interactions involved in dsRNA recognition and cleavage.
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PMID:New approaches to understanding double-stranded RNA processing by ribonuclease III purification and assays of homodimeric and heterodimeric forms of RNase III from bacterial extremophiles and mesophiles. 1916 41

Peripheral myelin protein 22 (PMP22) is a dose-sensitive, disease-associated protein primarily expressed in myelinating Schwann cells. Either reduction or overproduction of PMP22 can result in hereditary neuropathy, suggesting a requirement for correct protein expression for peripheral nerve biology. PMP22 is post-transcriptionally regulated and the 3'untranslated region (3'UTR) of the gene exerts a negative effect on translation. MicroRNAs (miRNAs) are small regulatory molecules that function at a post-transcriptional level by targeting the 3'UTR in a reverse complementary manner. We used cultured Schwann cells to demonstrate that alterations in the miRNA biogenesis pathway affect PMP22 levels, and endogenous PMP22 is subjected to miRNA regulation. GW-body formation, the proposed cytoplasmic site for miRNA-mediated repression, and Dicer expression, an RNase III family ribonuclease involved in miRNA biogenesis, are co-regulated with the differentiation state of Schwann cells. Furthermore, the levels of Dicer inversely correlate with PMP22, while the inhibition of Dicer leads to elevated PMP22. Microarray analysis of actively proliferating and differentiated Schwann cells, in conjunction with bioinformatics programs, identified several candidate PMP22-targeting miRNAs. Here we demonstrate that miR-29a binds and inhibits PMP22 reporter expression through a specific miRNA seed binding region. Over-expression of miR-29a enhances the association of PMP22 RNA with Argonaute 2, a protein involved in miRNA function, and reduces the steady-state levels of PMP22. In contrast, inhibition of endogenous miR-29a relieves the miRNA-mediated repression of PMP22. Correlation analyses of miR-29 and PMP22 in sciatic nerves reveal an inverse relationship, both developmentally and in post-crush injury. These results identify PMP22 as a target of miRNAs and suggest that myelin gene expression by Schwann cells is regulated by miRNAs.
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PMID:Peripheral myelin protein 22 is regulated post-transcriptionally by miRNA-29a. 1917 Jan 79

microRNAs (miRNAs) are generated from long primary (pri-) RNA polymerase II (Pol II)-derived transcripts by two RNase III processing reactions: Drosha cleavage of nuclear pri-miRNAs and Dicer cleavage of cytoplasmic pre-miRNAs. Here we show that Drosha cleavage occurs during transcription acting on both independently transcribed and intron-encoded miRNAs. We also show that both 5'-3' and 3'-5' exonucleases associate with the sites where co-transcriptional Drosha cleavage occurs, promoting intron degradation before splicing. We finally demonstrate that miRNAs can also derive from 3' flanking transcripts of Pol II genes. Our results demonstrate that multiple miRNA-containing transcripts are co-transcriptionally cleaved during their synthesis and suggest that exonucleolytic degradation from Drosha cleavage sites in pre-mRNAs may influence the splicing and maturation of numerous mRNAs.
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PMID:Primary microRNA transcripts are processed co-transcriptionally. 1917 42

RNA silencing is a common term for a group of mechanistically related pathways that produce and employ short non-coding RNA molecules to achieve sequence-specific gene regulation. The RNase III-enzyme Dicer produces small RNAs (smRNAs) in both microRNA (miRNA) and RNA interference (RNAi) pathways. miRNAs modulate physiological and developmental gene expression. They are genome-encoded, endogenous negative regulators of translation and mRNA stability originating from long primary transcripts with local hairpin structures. RNAi is triggered by the processing of long double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs), which mediate sequence-specific cleavage of nascent mRNAs. The third common class of repressive small RNAs, PIWI-associated RNAs (piRNAs), is produced in a Dicer-independent manner. Current data suggest that piRNAs protect the germline from mobile genome invaders such as transposons. A small RNA involved in RNA silencing associates with proteins in an effector ribonucleoprotein complex usually referred to as RNA-Induced Silencing Complex (RISC). Key components of RISC complexes are proteins of the Argonaute family, which determine RISC functions. During three days in May 2008, around two hundred scientists working on RNA silencing met at IMBA, Vienna for the 3(rd) Microsymposium on Small RNAs (Fig. 1) (www.imba.oeaw.ac.at/microsymposium) organized by Javier Martinez.
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PMID:miRNA, siRNA, piRNA: Knowns of the unknown. 1918 24

The RNA-mediated gene silencing pathways are evolutionarily conserved processes. They highlight a fundamental role of short RNAs in eukaryotic gene regulation and antiviral defense. Recently three distinct small RNA-directed silencing pathways are observed, such as the destruction of mRNA via siRNA, inhibition of mRNA translation via miRNA, and epigenetic gene silencing via siRNA. It was also found that in these pathways, the members of ribonuclease III family play important roles in diverse RNA maturation and decay. Here we investigated the evolution of RNase III nucleases, Dicer as representative, to further figure out the evolutionary relationship of these three gene silencing pathways. With the advantage of using genomic sequences as the subject in homolog search, in un-annotated genomic regions, we were able to detect possible candidates for 3 functional domains and genes of dicer and drosha. Moreover, we found that prokaryotes including eubacteria and archaea lack completely the PAZ domain of Dicer. These results show the taxonomic-dependent evolution of the RNA-mediated gene silencing pathways.
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PMID:The evolutionary study of small RNA-directed gene silencing pathways by investigating RNase III enzymes. 1939 76

RNA interference (RNAi) uses small RNA molecules to regulate transcriptional and post-transcriptional gene expression. In recent years, a number of structural studies provided insights into the molecular architecture and mechanism of functional modules of RNAi. Mechanisms of nucleic acid recognition and cleavage have been revealed by structural studies of proteins and their nucleic acid complexes involved in RNA biogenesis, for example, Argonaute, PIWI, RNase III, Dicer, Drosha, and DGCR8. While quite a few questions remain, an excellent structural and mechanistic overview of RNAi processes has already emerged. In this review, we examine functional modules and their assemblies in RNAi processes.
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PMID:Structural and functional modules in RNA interference. 1947 31

Small RNAs, including small interfering RNAs (siRNAs), microRNAs (miRNAs) and Piwi-associated interfering RNAs (piRNAs), are powerful gene expression regulators. This RNA-mediated regulation results in sequence-specific inhibition of gene expression by translational repression and/or mRNA degradation. siRNAs and miRNAs are generated by RNase III enzymes and subsequently loaded into Argonaute protein, a key component of the RNA induced silencing complex (RISC), to form the core of the RNA silencing machinery. RNA silencing acts as an ancient cell defense system against molecular parasites, such as transgenes, viruses and transposons. RNA silencing also plays an important role in the control of development. In plants, RNA silencing serves as a potent antiviral defense system. In response, many viruses have developed strategies to suppress RNA silencing. The striking sequence diversity among viral suppressors suggests that different viral suppressors could target different components of the RNA silencing machinery at different steps in different suppressing modes. Significant progresses have been made in this field for the past 5 years on the basis of structural information derived from RNase III family proteins, Dicer fragments and homologs, Argonaute homologs and viral suppressors. In this paper, we will review the current progress on the understanding of molecular mechanisms of RNA silencing; highlight the structural principles determining the protein-RNA recognition events along the RNA silencing pathways and the suppression mechanisms displayed by viral suppressors.
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PMID:A structural perspective of the protein-RNA interactions involved in virus-induced RNA silencing and its suppression. 1950 79

MicroRNAs (miRNAs) are a class of evolutionarily conserved small noncoding RNAs that are increasingly being recognized as important regulators of gene expression. The ribonuclease III enzyme Dicer is essential for the processing of miRNAs. CD1d-restricted invariant natural killer T (iNKT) cells are potent regulators of diverse immune responses. The role of Dicer-generated miRNAs in the development and function of immune regulatory iNKT cells is unknown. Here, we generated a mouse strain with a tissue-specific disruption of Dicer, and showed that lack of miRNAs after the deletion of Dicer by Tie2-Cre (expressed in hematopoietic cells and endothelial cells) interrupted the development and maturation of iNKT cells in the thymus and significantly decreased the number of iNKT cells in different immune organs. Thymic and peripheral iNKT cell compartments were changed in miRNA-deficient mice, with a significantly increased frequency of CD4(+)CD8(+) iNKT cells in the thymus and a significantly decreased frequency of CD4(+) iNKT cells in the spleen. MiRNA-deficient iNKT cells display profound defects in alpha-GalCer-induced activation and cytokine production. Bone marrow (BM) from miRNA-deficient mice poorly reconstituted iNKT cells compared to BM from WT mice. Also, using a thymic iNKT cell transfer model, we found that iNKT cell homeostasis was impaired in miRNA-deficient recipient mice. Our data indicate that miRNAs expressed in hematopoietic cells and endothelial cells are potent regulators of iNKT cell development, function, and homeostasis.
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PMID:Tie2cre-induced inactivation of the miRNA-processing enzyme Dicer disrupts invariant NKT cell development. 1950 35


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