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)

Chloroplast genomes in land plants harbor approximately 20 group II introns. Genetic approaches have identified proteins involved in the splicing of many of these introns, but the proteins identified to date cannot account for the large size of intron ribonucleoprotein complexes and are not sufficient to reconstitute splicing in vitro. Here, we describe an additional protein that promotes chloroplast group II intron splicing in vivo. This protein, RNC1, was identified by mass spectrometry analysis of maize (Zea mays) proteins that coimmunoprecipitate with two previously identified chloroplast splicing factors, CAF1 and CAF2. RNC1 is a plant-specific protein that contains two ribonuclease III (RNase III) domains, the domain that harbors the active site of RNase III and Dicer enzymes. However, several amino acids that are essential for catalysis by RNase III and Dicer are missing from the RNase III domains in RNC1. RNC1 is found in complexes with a subset of chloroplast group II introns that includes but is not limited to CAF1- and CAF2-dependent introns. The splicing of many of the introns with which it associates is disrupted in maize rnc1 insertion mutants, indicating that RNC1 facilitates splicing in vivo. Recombinant RNC1 binds both single-stranded and double-stranded RNA with no discernible sequence specificity and lacks endonuclease activity. These results suggest that RNC1 is recruited to specific introns via protein-protein interactions and that its role in splicing involves RNA binding but not RNA cleavage activity.
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PMID:A ribonuclease III domain protein functions in group II intron splicing in maize chloroplasts. 1769 27

A hallmark of RNA interference is the production of short double-stranded RNA (dsRNA) molecules 21-28 nucleotides in length by the specialized RNase III protein Dicer. Dicer enzymes uniquely generate RNA products of specific lengths by mechanisms that have not been fully elucidated. Here we show that the PAZ domain responsible for dsRNA end recognition confers this measuring ability through both its structural position and RNA-binding specificity. Point mutations define the dsRNA-binding surface and reveal a protein loop important for cleavage of substrates containing perfect or imperfect base pairing. On the basis of these results, we reengineered Dicer with a U1A RNA-binding domain in place of the PAZ domain to create an enzyme with altered end-recognition specificity and RNA product length. These results explain how Dicer functions as a molecular ruler and provide a structural basis for modifying its activity in cells.
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PMID:Structural determinants of RNA recognition and cleavage by Dicer. 1787 86

RNA-mediated gene silencing is recently emerged as a fundamental mechanism of regulation of gene expression in many organisms and tissues, with special emphasis with respect to the nervous system. With the aim to study the components of RNA silencing machinery, we have investigated the expression profile and localization of dicer protein RNase III endonuclease in cultures of post-mitotic neurons. Dicer catalyzes the processing of double-stranded RNAs (dsRNAs) into approximately 21-25 nucleotide-long small interfering (si)RNAs and micro (mi)RNAs, and it represents an essential step in the biogenesis of these small non-coding RNA molecules. We show that in rat primary neurons dicer is localized in the somatodendritic compartment, at the Golgi-reticulum area network level. This peculiar distribution was altered by brefeldin A treatment. Moreover the Golgi-reticulum dicer signal was observed also in primary astroglial cells. In addiction dicer was observed to be regulated during the embryogenesis and development in several tissues. In fact its expression is developmentally regulated in cultured cerebellar granule neurons. This is the first study in which dicer is shown preferentially distributed in the Golgi-reticulum area in post-mitotic terminally differentiated neuronal and glial cells and that its profile is modulated during maturation and development of in vitro cultured cerebellar granule neurons.
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PMID:Dicer expression and localization in post-mitotic neurons. 1788 88

Human Dicer contains two RNase III domains (RNase IIIa and RNase IIIb) that are responsible for the production of short interfering RNAs and microRNAs. These small RNAs induce gene silencing known as RNA interference. Here, we report the crystal structure of the C-terminal RNase III domain (RNase IIIb) of human Dicer at 2.0 A resolution. The structure revealed that the RNase IIIb domain can form a tightly associated homodimer, which is similar to the dimers of the bacterial RNase III domains and the two RNase III domains of Giardia Dicer. Biochemical analysis showed that the RNase IIIb homodimer can cleave double-stranded RNAs (dsRNAs), and generate short dsRNAs with 2 nt 3' overhang, which is characteristic of RNase III products. The RNase IIIb domain contained two magnesium ions per monomer around the active site. The distance between two Mg-1 ions is approximately 20.6 A, almost identical with those observed in bacterial RNase III enzymes and Giardia Dicer, while the locations of two Mg-2 ions were not conserved at all. We presume that Mg-1 ions act as catalysts for dsRNA cleavage, while Mg-2 ions are involved in RNA binding.
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PMID:Homodimeric structure and double-stranded RNA cleavage activity of the C-terminal RNase III domain of human dicer. 1792 Jun 23

microRNAs (miRNAs) regulate gene expression post-transcriptionally by targeting mRNAs for degradation or by inhibiting translation. Dicer is an RNase III endonuclease which processes miRNA precursors into functional 21-23 nucleotide RNAs that are subsequently incorporated into the RNA-induced silencing complex. miRNA-mediated gene regulation is important for organogenesis of a variety of tissues including limb, lung and skin. To gain insight into the roles of Dicer and miRNAs in mammalian skeletal muscle development, we eliminated Dicer activity specifically in the myogenic compartment during embryogenesis. Dicer activity is essential for normal muscle development during embryogenesis and Dicer muscle mutants have reduced muscle miRNAs, die perinatally and display decreased skeletal muscle mass accompanied by abnormal myofiber morphology. Dicer mutant muscles also show increased apoptosis and Cre-mediated loss of Dicer in Myod-converted myoblasts results in enhanced cell death. These observations demonstrate key roles for Dicer in skeletal muscle and implicate miRNAs as critical components required for embryonic myogenesis.
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PMID:Essential role for Dicer during skeletal muscle development. 1793 65

The ribonuclease III Dicer (Dcr1) has been shown to be required for chromosome segregation and gene silencing in Schizosaccharomyces pombe. These effects are thought to be transcriptional, mediated by formation and maintenance of heterochromatin, and guided by small RNAs derived from Dcr1 along a process known as RNA interference. In order to get further insights into the gene regulatory role of Dcr1, we performed comparative analyses of dcr1 knockout and wild-type fission yeast strains. Analysis of part of the soluble proteomes identified eight cellular proteins whose expression is under Dcr1 control, three of which are integral constituents of the glycolysis pathway. Further correlations with their respective mRNA transcript levels are compatible with the existence of a post-transcriptional gene regulatory mechanism involving Dcr1 or a Dcr1 complex. Experiments designed to identify components of Dcr1 complexes unveiled two novel Dcr1 interactors, namely the zinc finger protein Byr3 and the ribosomal protein L12. Consistently enriched in Dcr1 immune complexes, Byr3 and L12 may link Dcr1 to the transcriptional and translational machineries, respectively, and contribute to post-transcriptional gene regulation in fission yeast.
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PMID:Involvement of Dcr1 in post-transcriptional regulation of gene expression in Schizosaccharomyces pombe. 1798 3

In this study, we investigated an RNA (R-Psi-sgRNA) that suppresses HIV-1 replication. This RNA is expressed by a plasmid vector (pR-Psi-sgRNA-ter) that was constructed accidentally. To examine if this effect is caused by RNA interference, R-Psi-sgRNA was synthesized in vitro and treated with the Dicer enzyme, an important RNase III enzyme for RNA interference. The RNA was cleaved into fragments of approximately 20 nucleotides. We then performed an HIV-1 p24 assay with the RNA fragments to evaluate their effect on HIV-1 replication. HIV-1 replication was suppressed. We are now analyzing the sequences of the RNA fragments.
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PMID:Non-sequence specific RNA inhibition of HIV-1 replication. 1802 61

RNA interference is mediated by small interfering RNAs produced by members of the ribonuclease III (RNase III) family represented by bacterial RNase III and eukaryotic Rnt1p, Drosha and Dicer. For mechanistic studies, bacterial RNase III has been a valuable model system for the family. Previously, we have shown that RNase III uses two catalytic sites to create the 2-nucleotide (nt) 3' overhangs in its products. Here, we present three crystal structures of RNase III in complex with double-stranded RNA, demonstrating how Mg(2+) is essential for the formation of a catalytically competent protein-RNA complex, how the use of two Mg(2+) ions can drive the hydrolysis of each phosphodiester bond, and how conformational changes in both the substrate and the protein are critical elements for assembling the catalytic complex. Moreover, we have modelled a protein-substrate complex and a protein-reaction intermediate (transition state) complex on the basis of the crystal structures. Together, the crystal structures and the models suggest a stepwise mechanism for RNase III to execute the phosphoryl transfer reaction.
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PMID:A stepwise model for double-stranded RNA processing by ribonuclease III. 1804 82

MicroRNAs (miRNAs) are short regulatory RNAs that direct repression of their mRNA targets. The miRNA "seed"-nucleotides 2-7-establishes target specificity by mediating target binding. Accurate processing of the miRNA 5' end is thought to be under strong selective pressure because a shift by just one nucleotide in the 5' end of a miRNA alters its seed sequence, redefining its repertoire of targets (Figure 1). Animal miRNAs are produced by the sequential cleavage of partially double-stranded precursors by the RNase III endonucleases Drosha and Dicer, thereby generating a transitory double-stranded intermediate comprising the miRNA paired to its partially complementary miRNA* strand. Here, we report that in flies, the 5' ends of miRNAs and miRNA* strands are typically more precisely defined than their 3' ends. Surprisingly, the precision of the 5' ends of both miRNA and miRNA* sequences increases after Argonaute2 (Ago2) loading. Our data imply that either many miRNA* sequences are under evolutionary pressure to maintain their seed sequences-that is, they have targets-or that secondary constraints, such as the sequence requirements for loading small RNAs into functional Argonaute complexes, narrow the range of miRNA and miRNA 5' ends that accumulate in flies.
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PMID:Argonaute loading improves the 5' precision of both MicroRNAs and their miRNA* strands in flies. 1820 40

Cardiovascular disease is the leading cause of human morbidity and mortality. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy associated with heart failure. Here, we report that cardiac-specific knockout of Dicer, a gene encoding a RNase III endonuclease essential for microRNA (miRNA) processing, leads to rapidly progressive DCM, heart failure, and postnatal lethality. Dicer mutant mice show misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicate significantly reduced heart rates and decreased fractional shortening of Dicer mutant hearts. Consistent with the role of Dicer in animal hearts, Dicer expression was decreased in end-stage human DCM and failing hearts and, most importantly, a significant increase of Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions.
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PMID:Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. 1825 89


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