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:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RNA editing in the sleeping sickness parasite Trypanosoma brucei remodels mitochondrial transcripts by the addition and deletion of uridylates as specified by guide RNAs. Editing is catalyzed by at least three distinct approximately 20S multiprotein editosomes, all of which contain KREPB4, a protein with RNase III and Pumilio motifs. RNAi repression of KREPB4 expression in procyclic forms (PFs) strongly inhibited growth and in vivo RNA editing, greatly diminished the abundance of 20S editosomes, reduced cellular levels of editosome proteins, and generated approximately 5-10S editosome subcomplexes. Editing TUTase, exoUase, and RNA ligase activities were largely shifted from approximately 20S to approximately 5-10S fractions of cellular lysates. Insertion and deletion endonuclease activities in approximately 20S fractions were strongly reduced upon KREPB4 repression but were not detected in the 5-10S subcomplex fraction. Abundance of MRP1 and RBP16 proteins, which appear to be involved in RNA processing but are not components of the 20S editosome, was unaltered upon KREPB4 repression. These data suggest that KREPB4 is important for the structural integrity of approximately 20S editosomes, editing endonuclease activity, and the viability of PF T. brucei cells.
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PMID:An essential role of KREPB4 in RNA editing and structural integrity of the editosome in Trypanosoma brucei. 1736 11

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

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

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

Trypanosoma brucei has three distinct approximately 20S editosomes that catalyze RNA editing by the insertion and deletion of uridylates. Editosomes with the KREN1 or KREN2 RNase III type endonucleases specifically cleave deletion and insertion editing site substrates, respectively. We report here that editosomes with KREPB2, which also has an RNase III motif, specifically cleave cytochrome oxidase II (COII) pre-mRNA insertion editing site substrates in vitro. Conditional repression and mutation studies also show that KREPB2 is an editing endonuclease specifically required for COII mRNA editing in vivo. Furthermore, KREPB2 expression is essential for the growth and survival of bloodstream forms. Thus, editing in T. brucei requires at least three compositionally and functionally distinct approximately 20S editosomes, two of which distinguish between different insertion editing sites. This unexpected finding reveals an additional level of complexity in the RNA editing process and suggests a mechanism for how the selection of sites for editing in vivo is controlled.
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PMID:RNA editing in Trypanosoma brucei requires three different editosomes. 1795 57

Sweet potato chlorotic stunt virus (genus Crinivirus) belongs to the family Closteroviridae, members of which have a conserved overall genomic organization but are variable in gene content. In the bipartite criniviruses, heterogeneity is pronounced in the 3'-proximal region of RNA1, which in sweet potato chlorotic stuat virus (SPCSV) encodes two novel proteins, RNase3 (RNase III endonuclease) and p22 (RNA silencing suppressor). This study showed that two Ugandan SPCSV isolates contained the p22 gene, in contrast to three isolates of the East African strain from Tanzania and Peru and an isolate of the West African strain from Israel, which were missing a 767 nt fragment of RNA1 that included the p22 gene. Regardless of the presence of p22, all tested SPCSV isolates acted synergistically with potyvirus sweet potato feathery mottle virus (SPFMV; genus Potyvirus, family Potyviridae) in co-infected sweetpotato plants (Ipomoea batatas), which greatly enhanced SPFMV titres and caused severe sweetpotato virus disease (SPVD). Therefore, the results indicate that any efforts to engineer pathogen-derived RNA silencing-based resistance to SPCSV and SPVD in sweetpotato should not rely on p22 as the transgene. The data from this study demonstrate that isolates of this virus species can vary in the genes encoding RNA silencing suppressor proteins. This study also provides the first example of intraspecific variability in gene content of the family Closteroviridae and may be a new example of the recombination-mediated gene gain that is characteristic of virus evolution in this virus family.
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PMID:Analysis of gene content in sweet potato chlorotic stunt virus RNA1 reveals the presence of the p22 RNA silencing suppressor in only a few isolates: implications for viral evolution and synergism. 1819 89

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

Dicer, an RNase III type endonuclease, is the key enzyme involved in RNA interference (RNAi) and microRNA (miRNA) pathways. It is required for biogenesis of miRNAs and small interfering RNAs (siRNAs), and also plays an important role in an effector step of RNA silencing, the RNA-induced silencing complex (RISC) assembly. In this article we describe different functions of Dicer in posttranscriptional regulation. We review the current knowledge about Dicers in different organisms and the functions of individual domains of the enzyme. We also discuss information about Dicer-associated proteins and their role in the biogenesis of small RNAs and assembly of RISC.
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PMID:Role of Dicer in posttranscriptional RNA silencing. 1826 40

MicroRNAs (miRNAs) are small, highly conserved molecules that have been shown to regulate the expression of genes by binding to specific target mRNAs. Dicer, an RNase III endonuclease, is essential for the production and function of mature miRNAs, and removal of Dicer has been shown to disrupt many developmental processes. In this study, Dicer was removed specifically from the retina using a floxed Dicer conditional allele and the retinal Chx10Cre transgene. Retinal Dicer knock-out mice displayed a reproducible inability to respond to light. In addition, morphological defects were observed with the formation of photoreceptor rosettes at postnatal day 16, which progressed to more general cellular disorganization and widespread degeneration of retinal cell types as the animals aged. This was accompanied by concomitant decrease in both scotopic and photopic electroretinogram (ERG) responses. Interestingly, removing a single allele of Dicer resulted in ERG deficits throughout life but not to morphological abnormalities. Northern blot analysis of Dicer-depleted retinas showed a decrease in several miRNAs. The observation that progressive retinal degeneration occurred after removal of Dicer raises the possibility that miRNAs are involved in retinal neurodegenerative disorders.
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PMID:Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina. 1846 41

U-insertion/deletion RNA editing in the single mitochondrion of kinetoplastids, an ancient lineage of eukaryotes, is a unique mRNA maturation process needed for translation. Multisubunit editing complexes recognize many pre-edited mRNA sites and modify them via cycles of three catalytic steps: guide RNA (gRNA)-directed cleavage, insertion or deletion of uridylates at the 3'-terminus of the upstream cleaved piece, and ligation of the two mRNA pieces. While catalytic and many structural protein subunits of these complexes have been identified, the mechanisms and basic determinants of substrate recognition are still poorly understood. This study defined relatively simple single- and double-stranded determinants for association and gRNA-directed cleavage. To this end, we used an electrophoretic mobility shift assay to directly score the association of purified editing complexes with RNA ligands, in parallel with UV photocrosslinking and functional studies. The cleaved strand required a minimal 5' overhang of 12 nt and an approximately 15-bp duplex with gRNA to direct the cleavage site. A second protruding element in either the cleaved or the guide strand was required unless longer duplexes were used. Importantly, the single-stranded RNA requirement for association can be upstream or downstream of the duplex, and the binding and cleavage activities of purified editing complexes could be uncoupled. The current observations together with our previous reports in the context of purified native editing complexes show that the determinants for association, cleavage and full-round editing gradually increase in complexity as these stages progress. The native complexes in these studies contained most, if not all, known core subunits in addition to components of the MRP complex. Finally, we found that the endonuclease KREN1 in purified complexes photocrosslinks with a targeted editing site. A model is proposed whereby one or more RNase III-type endonucleases mediate the initial binding and scrutiny of potential ligands and subsequent catalytic selectivity triggers either insertion or deletion editing enzymes.
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PMID:Determinants for association and guide RNA-directed endonuclease cleavage by purified RNA editing complexes from Trypanosoma brucei. 1857 90


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