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DDX6 and its orthologs as modulators of cellular and viral RNA expression

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DDX6 (Rck/p54), a member of the DEAD‐box family of helicases, is highly conserved from unicellular eukaryotes to vertebrates. Functions of DDX6 and its orthologs in dynamic ribonucleoproteins contribute to global and transcript‐specific messenger RNA (mRNA) storage, translational repression, and decay during development and differentiation in the germline and somatic cells. Its role in pathways that promote mRNA‐specific alternative translation initiation has been shown to be linked to cellular homeostasis, deregulated tissue development, and the control of gene expression in RNA viruses. Recently, DDX6 was found to participate in mRNA regulation mediated by miRNA‐mediated silencing. DDX6 and its orthologs have versatile functions in mRNA metabolism, which characterize them as important post‐transcriptional regulators of gene expression. WIREs RNA 2014, 5:659–678. doi: 10.1002/wrna.1237 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability

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Domain organization and arrangement of RNA helicase motifs in DDX6 and orthologs. (a) DEAD‐box RNA helicase motifs, which contribute to ATP binding and hydrolysis (Q, I, II, III, and VI) or RNA binding (Ia, Ib, IV, and V), are depicted in red or blue, respectively. The Q‐motif and the conserved phenylalanine 17 residues upstream are specific for DEAD‐box RNA helicases. Numbers between the motifs indicate the length of the spacer or the N‐ and C‐termini of the different orthologs. (b) The DEAD‐box helicase motifs are assigned in the crystal structure of Saccharomyces cerevisiae Dhh1 (PDB 4BRU). (c) Surface representation of Dhh1. Motifs involved in ATP binding and hydrolysis are depicted red, and motifs that contribute to RNA binding are in blue.
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Schematic representation of DDX6 functions. (a) Possible mechanisms of DDX6‐mediated cellular mRNA translation control. DDX6 is recruited to the mRNA by a transcript‐specific repressor complex. DDX6 catalyzes ATP‐dependent mRNA unwinding, which facilitates masking by additional DDX6 molecules. The repressed mRNA is recruited to processing bodies (PBs), where it is either targeted to degradation or stored for (re)‐entry to translation. (b) DDX6 alters cellular mRNA internal ribosome entry site (IRES) activity by modulating the IRES structure and IRES–protein complexes, resulting in activation or repression of IRES‐mediated translation initiation. (c) Influences of DDX6 on different stages of the RNA virus life cycle, ranging from viral RNA translation to replication of the RNA genome and viral capsid assembly were shown for hepatitis C virus (HCV), dengue virus (DENV), human immunodeficiency type 1 virus (HIV‐1), and human foamy virus (FV). (d) DDX6 is implicated to contribute to miRNA‐induced mRNA silencing (see text for details).
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Protein sequence alignment of DDX6 and orthologous proteins. Alignment of DDX6 orthologs in Saccharomyces cerevisiae (Dhh1, NCBI CAA98734.1), Schizosaccharomyces pombe (Ste13, NCBI CAA22882.1), Trypanosoma brucei (tDhh1, NCBI XP_822647.1), Plasmodium berghei (DOZI, PlasmoDB PBANKA_121770), Spisula solidissima (p47, NCBI AAK85400.1), Caenorhabditis elegans (CGH‐1, NCBI NP_498646.1), Drosophila melanogaster (Me31B, NCBI P23128.3), Xenopus laevis (Xp54, NCBI NP_001083721.1), Mus musculus (mRCK/p54, NCBI NP_851841.2), and Homo sapiens (DDX6, NCBI NP_004388.2). DEAD‐box RNA helicase motifs are depicted in red, and conserved amino acid residues are highlighted in yellow. Alignment was performed with ClustalW.
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RNA Turnover and Surveillance > Regulation of RNA Stability
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes

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