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)

Dicer, an RNase III enzyme, initiates RNA interference by processing precursor dsRNAs into mature microRNAs and small-interfering RNAs. It is also involved in loading and activation of the RNA-induced silencing complex. Here, we report the crystal structures of a catalytically active fragment of mouse Dicer, containing the RNase IIIb and dsRNA binding domains, in its apo and Cd(2+)-bound forms, at 1.68- and 2.8-A resolution, respectively. Models of this structure with dsRNA reveal that a lysine residue, highly conserved in Dicer RNase IIIa and IIIb domains and in Drosha RNase IIIb domains, has the potential to participate in the phosphodiester bond cleavage reaction by stabilizing the transition state and leaving group of the scissile bond. Mutational and enzymatic assays confirm the importance of this lysine in dsRNA cleavage, suggesting that this lysine represents a conserved catalytic residue of Dicers. The structures also reveals a approximately 45-aa region within the RNase IIIb domain that harbors an alpha-helix at the N-terminal half and a flexible loop at the C-terminal half, features not present in previously reported structures of homologous RNase III domains from either bacterial RNase III enzymes or Giardia Dicer. N-terminal residues of this alpha-helix have the potential to engage in minor groove interaction with dsRNA substrates.
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PMID:Structural and biochemical insights into the dicing mechanism of mouse Dicer: a conserved lysine is critical for dsRNA cleavage. 1826 34

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

Members of the Ribonuclease III (RNase III) family are double-stranded (ds) RNA-specific endoribonucleases, characterized by a signature motif in their active centers and a 2-nucleotide (nt) 3' overhang in their products. Dicer functions as a dsRNA-processing enzyme, producing small interfering RNA (siRNA) of approx. 24 nt in length (approx. 20-basepair RNA duplex with a 2-nt 3' overhang on each end). Bacterial RNase III functions not only as a processing enzyme, but also as a binding protein that binds dsRNA without cleaving it. As a processing enzyme it produces siRNA-like RNA of approx. 13 nt in length (approx. 9-basepair duplex with a 2-nt 3' overhang on each end) as well as various types of mature RNA. Dicer is structurally most complicated member of the family; bacterial RNase III is comparatively much simpler. One structure is known for Dicer in its RNA-free form (MacRae, Zhou, Li, Repic, Brooks, Cande, Adams, and Doudna, Science 311:195-198); many structures are available for bacterial RNase III, including the first catalytic complex of the entire family (Gan, Tropea, Austin, Court, Waugh, and Ji, Cell 124:355-366). In light of the structural and biochemical information on the RNase III proteins and the structure of a non-Dicer PAZ (Piwi Argonaute Zwille) domain in complex with a 7-basepair RNA duplex with a 2-nt 3' overhang on each end (Ma, Ye, and Patel, Nature 429:318-322), the structure and function of Dicer is being elucidated.
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PMID:The mechanism of RNase III action: how dicer dices. 1826 41

The microRNA (miRNA) pathway represents an integral component of the gene regulation circuitry that controls development. In recent years, the role of miRNAs in embryonic stem (ES) cells and mammalian embryogenesis has begun to be explored. A few dozens of miRNAs expressed in mammalian ES cells, either exclusively or nonexclusively, have been cloned. The overall role of miRNAs in ES cells and embryonic development has been assessed by examining the effect of knocking out Dicer, an RNase III enzyme required for miRNA and small interfering RNA biogenesis, as well as DGCR8, a nuclear protein specifically involved in miRNA biogenesis. In addition, the role of a cluster of miRNAs specifically expressed in ES cells, the miR-290-295 group, has been investigated by the knock-out approach. These analyses have revealed the crucial role of miRNAs in ES cell differentiation, lineage specification, and organogenesis, especially neurogenesis and cardiogenesis. Systematic investigation of the role of miRNAs in ES cells and embryos will allow us to find missing pieces of the mosaic of early development.
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PMID:Piecing together the mosaic of early mammalian development through microRNAs. 1827 16

The interaction between human immunodeficiency virus type 1 (HIV-1) and RNA silencing pathways is complex and multifaceted. Essential for efficient viral transcription and supporting Tat-mediated transactivation of viral gene expression, the trans-activation responsive (TAR) element is a structured RNA located at the 5' end of all transcripts derived from HIV-1. Here, we report that this element is a source of microRNAs (miRNAs) in cultured HIV-1-infected cell lines and in HIV-1-infected human CD4+ T lymphocytes. Using primer extension and ribonuclease (RNase) protection assays, we delineated both strands of the TAR miRNA duplex deriving from a model HIV-1 transcript, namely miR-TAR-5p and miR-TAR-3p. In vitro RNase assays indicate that the lack of a free 3' extremity at the base of TAR may contribute to its low processing reactivity in vivo. Both miR-TAR-5p and miR-TAR-3p down-regulated TAR miRNA sensor activity in a process that required an integral miRNA-guided RNA silencing machinery. miR-TAR-3p exerted superior gene downregulatory effects, probably due to its preferential release from HIV-1 TAR RNA by the RNase III Dicer. Our study suggests that the TAR element of HIV-1 transcripts releases functionally competent miRNAs upon asymmetrical processing by Dicer, thereby providing novel insights into viral miRNA biogenesis.
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PMID:Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element. 1829 84

MicroRNAs are a group of small non-coding RNAs approximately 22 nucleotides in length. Recent work has shown differential expression of mature microRNAs in human cancers. Production and function of microRNAs require coordinated processing by proteins of the microRNA machinery. Dicer and Drosha (RNase III endonucleases) are essential components of the microRNA machinery. Recently, the ribosome anti-association factor eIF6 has also been found to have a role in microRNA-mediated post-transcriptional silencing. We characterized the alterations in the expression of genes encoding proteins of microRNA machinery in ovarian serous carcinoma. Protein expression of eIF6 and Dicer was quantified in a tissue microarray of 66 ovarian serous carcinomas. Dicer, Drosha and eIF6 mRNA expression was analysed using quantitative reverse transcription-PCR on an independent set of 50 formalin-fixed, paraffin-embedded ovarian serous carcinoma samples. Expression profiles of eIF6 and Dicer were correlated with clinicopathological and patient survival data. We provide definitive evidence that eIF6 and Dicer are both upregulated in a significant proportion of ovarian serous carcinomas and are associated with specific clinicopathological features, most notably low eIF6 expression being associated with reduced disease-free survival. The status of eIF6 and proteins of the microRNA machinery may help predict toxicity and susceptibility to future interfering RNA-based therapy.
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PMID:Altered eIF6 and Dicer expression is associated with clinicopathological features in ovarian serous carcinoma patients. 1832 11

The late steps of both 16S and 5S ribosomal RNA maturation in the Gram-positive bacterium Bacillus subtilis have been shown to be catalysed by ribonucleases that are not present in the Gram-negative paradigm, Escherichia coli. Here we present evidence that final maturation of the 5' and 3' extremities of B. subtilis 23S rRNA is also performed by an enzyme that is absent from the Proteobacteria. Mini-III contains an RNase III-like catalytic domain, but curiously lacks the double-stranded RNA binding domain typical of RNase III itself, Dicer, Drosha and other well-known members of this family of enzymes. Cells lacking Mini-III accumulate precursors and alternatively matured forms of 23S rRNA. We show that Mini-III functions much more efficiently on precursor 50S ribosomal subunits than naked pre-23S rRNA in vitro, suggesting that maturation occurs primarily on assembled subunits in vivo. Lastly, we provide a model for how Mini-III recognizes and cleaves double-stranded RNA, despite lacking three of the four RNA binding motifs of RNase III.
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PMID:Mini-III, an unusual member of the RNase III family of enzymes, catalyses 23S ribosomal RNA maturation in B. subtilis. 1836 98

RNA interference (RNAi) is a form of posttranscriptional gene silencing mediated by microRNA (miRNA) and small interfering RNA (siRNA). In Drosophila melanogaster, the RNase III enzymes Dicer-1 and Dicer-2 generate miRNA and siRNA, respectively. We describe the methods for the expression, purification, and analysis of recombinant Dicer-1 and Dicer-2 enzymes. Our studies demonstrate that Dicer-1 and Dicer-2 display different substrate specificities and ATP requirements.
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PMID:Expression, purification, and analysis of recombinant Drosophila Dicer-1 and Dicer-2 enzymes. 1836 75

MicroRNAs (miRNAs) are generated from primary transcripts through sequential processing by two RNase III enzymes, Drosha and Dicer, in association with other proteins. This maturation is essential for their function as post-transcriptional regulators. Notably, Dicer is also a component of RNA-induced silencing complexes, which incorporate either miRNA or small interfering RNA (siRNA) as guides to target specific mRNAs. In zebrafish, processed miRNAs belonging to the miR-430 family have previously been shown to promote deadenylation and degradation of maternal mRNAs during early embryogenesis. We show that injection of one-cell-stage zebrafish embryos with siRNA causes a significant reduction in the endogenous levels of processed miR-430 and other miRNAs, leading to unspecific developmental defects. Coinjection of siRNA with preprocessed miR-430 efficiently rescued development. This indicates that the abnormalities generally observed in siRNA-treated zebrafish embryos could be due to inhibition of miR-430 processing and/or activity. Our results also suggest that the miRNA pathway in mammals, under some experimental or therapeutic conditions, may be affected by siRNA.
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PMID:Treatment with small interfering RNA affects the microRNA pathway and causes unspecific defects in zebrafish embryos. 1838 79

MicroRNAs (miRNAs) are small noncoding RNAs that can act to repress target mRNAs by suppressing translation and/or reducing mRNA stability. Although it is clear that miRNAs and Dicer, an RNase III enzyme that is central to the production of mature miRNAs, have a role in the early development of neurons, their roles in the postmitotic neuron in vivo are largely unknown. To determine the roles of Dicer in neurons, we ablated Dicer in dopaminoceptive neurons. Mice that have lost Dicer in these cells display a range of phenotypes including ataxia, front and hind limb clasping, reduced brain size, and smaller neurons. Surprisingly, dopaminoceptive neurons without Dicer survive over the life of the animal. The lack of profound cell death contrasts with other mouse models in which Dicer has been ablated. These studies highlight the complicated nature of Dicer ablation in the brain and provide a useful mouse model for studying dopaminoceptive neuron function.
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PMID:Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration. 1838 71


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