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The role of the DEAD‐box RNA helicase DDX3 in mRNA metabolism

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Abstract DDX3 belongs to the DEAD‐box proteins, a large family of ATP‐dependent RNA helicases that participate in all aspects of RNA metabolism. Human DDX3 is a component of several messenger ribonucleoproteins that are found in the spliceosome, the export and the translation initiation machineries but also in different cytoplasmic mRNA granules. DDX3 has been involved in several cellular processes such as cell cycle progression, apoptosis, cancer, innate immune response, and also as a host factor for viral replication. Interestingly, not all these functions require the catalytic activities of DDX3 and thus, the precise roles of this apparently multifaceted protein remain largely obscure. The aim of this review is to provide a rapid and critical overview of the structure and functions of DDX3 with a particular emphasis on its role during mRNA metabolism. WIREs RNA 2013, 4:369–385. doi: 10.1002/wrna.1165 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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DEAD‐box RNA helicases and mechanisms of RNA duplex unwinding. (a) Schematic representation, not to scale, showing domains and motifs common to the DEAD‐box family. The catalytic helicase core is composed of two RecA‐like domains (domain 1 and domain 2), which contain conserved motifs involved in ATP binding (blue), RNA binding (brown), and linking of ATP and RNA binding (green). The variable N‐ and the C‐terminus regions are also indicated. (b) Mechanism of RNA duplex unwinding by local strand separation (left panel) or by translocation (right panel). The unwinding mechanism by local strand separation is characteristic of DEAD‐box proteins. Here, the RNA helicase in its ATP‐bound (red star) closed conformation is loaded directly onto the RNA duplex without polarity or position preference. Protein loading can occur as protomers and is greatly facilitated by unpaired regions (as indicated in the figure by discontinued lines). Upon loading, the RNA duplex is locally destabilized resulting in the reduction of the base‐paired nucleotides and the subsequent dissociation of both stands. The local strand separation process requires ATP binding but is independent of ATP hydrolysis. ATP hydrolysis induces dissociation and recycling of the RNA helicase. Constant rates of unwinding by local strand separation are affected by the length and stability of the RNA duplex and thus, some duplexes require more than one cycle of DEAD‐box protein loading/dissociation. The unwinding mechanism by translocation is characteristic of DNA and RNA helicases such as members of the Upf1‐like and DEAH/RHA groups (right panel). In this process, the ATP‐bound helicase is loaded (as a monomer or multimer) on one strand and upon multiple consecutives steps of ATP hydrolysis it translocates to the opposite direction resulting in the dissociation of the complementary strand. Both processes are very simplified in this figure and readers are referred to very interesting and detailed reviews on the duplex unwinding mechanisms employed by RNA helicases.

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Different models for the role of DDX3 in translation initiation. (a) DDX3 sequesters eIF4E from its binding to eIF4G resulting in the disruption of the eIF4F complex and the blockage of cap‐dependent translation. This process is independent from ATP binding and hydrolysis. (b) DDX3 interacts with eIF3 and the 40S ribosomal subunit to promote 80S ribosome assembly. This process is independent from ATP binding and hydrolysis. (c) DDX3 promotes ribosomal scanning of selected mRNAs that exhibit a structured 5′‐UTR. This process is ATP‐dependent and requires the unwinding activity. (d) DDX3 is required for translation of selected mRNAs carrying structures close to the m7GTP cap moiety. This process is ATP‐dependent and occurs prior to ribosomal scanning.

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Human DDX3 and its orthologs. Sequence alignment of human DDX3 (AAC34298.1) and its homologs in chicken (NP_001025971.1), frog (An3, NP_001095245.1), zebrafish (CAQ14635.1), fruit fly (belle, AAF54262.1), worm (LAF‐1, CCG28150.1), and yeast (Ded1, CAA99419.1). The N‐terminus, helicase domains 1 and 2 and the C‐terminus are indicated. The highly conserved catalytic motifs within the helicase core are illustrated with color boxes (blue, brown, or green) depending on the function indicated in Figure (a). The highly conserved eIF4E‐binding motif within the N‐terminal region and the less conserved 10‐amino acid insertion within domain 1 are indicated in green and red brackets, respectively. Alignment was carried out using Clustal Omega at http://www.ebi.ac.uk/Tools/msa/clustalo/.

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