Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.3 (RNase III)
 1,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small RNA-mediated gene silencing (RNA silencing) has emerged as a major regulatory pathway in eukaryotes. Identification of the key factors involved in this pathway has been a subject of rigorous investigation in recent years. In humans, small RNAs are generated by Dicer and assembled into the effector complex known as RNA-induced silencing complex (RISC) by multiple factors including hAgo2, the mRNA-targeting endonuclease, and TRBP (HIV-1 TAR RNA-binding protein), a dsRNA-binding protein that interacts with both Dicer and hAgo2. Here we describe an additional dsRNA-binding protein known as PACT, which is significant in RNA silencing. PACT is associated with an approximately 500 kDa complex that contains Dicer, hAgo2, and TRBP. The interaction with Dicer involves the third dsRNA-binding domain (dsRBD) of PACT and the N-terminal region of Dicer containing the helicase motif. Like TRBP, PACT is not required for the pre-microRNA (miRNA) cleavage reaction step. However, the depletion of PACT strongly affects the accumulation of mature miRNA in vivo and moderately reduces the efficiency of small interfering RNA-induced RNA interference. Our study indicates that, unlike other RNase III type proteins, human Dicer may employ two different dsRBD-containing proteins that facilitate RISC assembly.
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PMID:The role of PACT in the RNA silencing pathway. 1642 7

The double-stranded (ds) RNA binding proteins, TRBP and PACT bind the interferon-induced protein kinase PKR and dsRNA. TRBP inhibits, whereas PACT activates PKR. They have two dsRNA binding domains (dsRBDs) and a C-terminal domain that does not bind RNA. All three domains show a strong homology between the two proteins. Interaction assays by in vitro binding, yeast two-hybrid, and immunoprecipitations show that TRBP and PACT form heterodimers in the absence of dsRNA. In cells, TRBP and PACT colocalize in specific dots of the perinuclear space. Analysis of the individual domains shows that the two dsRBDs of each protein interact with each other. In contrast, the C-terminal domain of PACT homodimerizes and interacts with its homologous region in TRBP, but the same domain in TRBP does not homodimerize. Because the C-terminal domain in TRBP binds to the tumor suppressor Merlin, the RNase III Dicer and PACT, we name it the Merlin Dicer PACT liaison (Medipal) domain. Based on known interactions Medipal is defined as aminoacids 228-366 in TRBP and 195-313 in PACT. TRBP-PACT interaction correlates with an absence of eIF2alpha activation by PACT, suggesting that the heterodimer does not activate PKR. We propose that the Medipal domain mediates specialized functions through protein-protein interactions and contributes to the RNA interference pathway and to PKR activation.
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PMID:Interactions between the double-stranded RNA-binding proteins TRBP and PACT define the Medipal domain that mediates protein-protein interactions. 1842 Dec 56

The dsRNA binding protein (DRBP) family comprise one or more evolutionarily conserved dsRNA-binding domains (DRBD) of approximately 65-68 amino acids, are found in both eukaryotes and prokaryotes and are even encoded by plants and viruses. DRBP's do not recognize specific nucleotide sequences and primarily interact with approximately 11-16 base pairs present within A-form double helix RNAs, which can include ssRNA's with extensive secondary structure. The DRBP family include TRBP (TAR RNA binding protein), PKR (protein kinase activated by dsRNA), PACT (Protein Activator of PKR), ADAR (Adenosine deaminases acting on RNA), and the RNase III family including DICER, which collectively play important roles in mRNA elongation, RNA interference (RNAi), mRNA editing, stability, splicing and/or export and translation. Here, we focus on the role of DRBP's referred to as the NFARs (Nuclear Factors associated with dsRNA) which are translated from two major alternatively spliced products encoded from a single gene. Evidence indicates that the NFAR proteins play crucial roles in mRNA post-transcriptional regulation, including mRNA stability, export and translation and may also have an important function in host defense.
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PMID:The NFAR's (nuclear factors associated with dsRNA): evolutionarily conserved members of the dsRNA binding protein family. 1910 22

RIG-I, a virus sensor that triggers innate antiviral response, is a DExD/H box RNA helicase bearing structural similarity with Dicer, an RNase III-type nuclease that mediates RNA interference. Dicer requires double-stranded RNA-binding protein partners, such as PACT, for optimal activity. Here we show that PACT physically binds to the C-terminal repression domain of RIG-I and potently stimulates RIG-I-induced type I interferon production. PACT potentiates the activation of RIG-I by poly(I:C) of intermediate length. PACT also cooperates with RIG-I to sustain the activation of antiviral defense. Depletion of PACT substantially attenuates viral induction of interferons. The activation of RIG-I by PACT does not require double-stranded RNA-dependent protein kinase or Dicer, but is mediated by a direct interaction that leads to stimulation of its ATPase activity. Our findings reveal PACT as an important component in initiating and sustaining the RIG-I-dependent antiviral response.
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PMID:The double-stranded RNA-binding protein PACT functions as a cellular activator of RIG-I to facilitate innate antiviral response. 2150 29

One of the cellular functions of the ribonuclease Dicer is to process microRNA precursors (pre-miRNAs) into mature microRNAs (miRNAs). Human Dicer performs this function in cooperation with its protein partners, AGO2, PACT and TRBP. The exact role of these accessory proteins in Dicer activity is still poorly understood. In this study, we used the northern blotting technique to investigate pre-miRNA cleavage efficiency and specificity after depletion of AGO2, PACT and TRBP by RNAi. The results showed that the inhibition of either Dicer protein partner substantially affected not only miRNA levels but also pre-miRNA levels, and it had a rather minor effect on the specificity of Dicer cleavage. The analysis of the Dicer cleavage products generated in vitro revealed the presence of a cleavage intermediate when pre-miRNA was processed by recombinant Dicer alone. This intermediate was not observed during pre-miRNA cleavage by endogenous Dicer. We demonstrate that AGO2, PACT and TRBP were required for the efficient functioning of Dicer in cells, and we suggest that one of the roles of these proteins is to assure better synchronization of cleavages triggered by two RNase III domains of Dicer.
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PMID:The role of Dicer protein partners in the processing of microRNA precursors. 2216 34