The current understanding of Ded1p/DDX3 homologs from yeast to human

Tarn, Woan‐Yuh

doi:10.4161/rna.6.1.7440

Cited by 85 publications

(82 citation statements)

References 37 publications

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“…Human DDX3 and its homologs in other species are multifunctional RNA helicases, and all can participate in translational control (3,6,9,16,25,27). However, the exact role of mammalian DDX3 in translation has been disputed (41,47). We observed in our previous and present studies that knockdown of DDX3 by RNA interference in HeLa cells neither impaired de novo global protein synthesis (25) nor affected polysome profiles (see Fig.…”

Section: Discussionmentioning

confidence: 55%

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DDX3 Regulates Cell Growth through Translational Control of Cyclin E1

Lai

Chang

Shieh

et al. 2010

Molecular and Cellular Biology

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157

175

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DDX3 belongs to the DEAD box family of RNA helicases, but the details of its biological function remain largely unclear. Here we show that knockdown of DDX3 expression impedes G 1 /S-phase transition of the cell cycle. To know how DDX3 may act in cell cycle control, we screened for cellular mRNA targets of DDX3. Many of the identified DDX3 targets encoded cell cycle regulators, including G 1 /S-specific cyclin E1. DDX3 depletion specifically downregulates translation of cyclin E1 mRNA. Moreover, our data suggest that DDX3 participates in translation initiation of targeted mRNAs as well as in cell growth control via its RNA helicase activity. Consistent with these findings, we show that in the temperature-sensitive DDX3 mutant hamster cell line tsET24, cyclin E1 expression is downregulated at a nonpermissive temperature that inactivates mutant DDX3. Taken together, our results indicate that DDX3 is critical for translation of cyclin E1 mRNA, which provides an alternative mechanism for regulating cyclin E1 expression during the cell cycle.The DEAD box family of RNA helicases plays diverse roles in eukaryotic gene expression, including transcriptional and posttranscriptional regulation (8,40). These helicases contain a highly conserved catalytic core domain that mediates ATP binding, in addition to their ATPase and helicase activities. They are presumed to function in unwinding RNA duplexes or remodeling RNA-protein complexes in an ATP-dependent manner. However, their cellular functions and localization may be defined largely by the divergent sequences flanking the catalytic core domain.Human DDX3 is a DEAD box RNA helicase that participates in various aspects of mRNA metabolism, including translation. The role of DDX3 in translational control is phylogenetically conserved (47). The DDX3 homolog in Saccharomyces cerevisiae, Ded1, participates in translation initiation (6, 9). Analogously, in the fission yeast Schizosaccharomyces pombe, Ded1 is implicated in translational control of two B-type cyclin genes, Cig2 and Cdc13, whose mRNAs contain a complex structure in the 5Ј untranslated region (5Ј UTR) (16). Indeed, Ded1 facilitates efficient RNA duplex unwinding, thus supporting its role in ribosome scanning at the translation initiation step (32). We recently reported that although DDX3 is dispensable for general mRNA translation, it is required for efficient translation of mRNAs that contain a long or structured 5Ј UTR (25). How the biochemical activity of DDX3 contributes to its function, however, remains unclear.In this study, we found that DDX3 targets the mRNA encoding the cell cycle regulator cyclin E1. The eukaryotic cell cycle is driven by a series of cyclin-dependent kinases (Cdks), which are activated via association with their respective cyclin partners (31). Cyclins D and E are specific for cell cycle progression from G 1 to S phase. In early G 1 phase, activated cyclin D-Cdk4/6 phosphorylates the retinoblastoma protein (pRb), which in turn releases E2F from the E2F-pRb complex and stimulates E2F-mediate...

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Section: Discussionmentioning

confidence: 55%

“…The role of DDX3 in translational control is phylogenetically conserved (47). The DDX3 homolog in Saccharomyces cerevisiae, Ded1, participates in translation initiation (6,9).…”

mentioning

confidence: 99%

DDX3 Regulates Cell Growth through Translational Control of Cyclin E1

Lai

Chang

Shieh

et al. 2010

Molecular and Cellular Biology

Self Cite

157

175

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“…67 DDX3 was later found to associate with some key members of the translation initiation machinery and to participate in translation of a subset of cellular and viral mRNAs carrying structured 5 0 -UTRs. 59,68,69 However, unlike its yeast ortholog, DDX3 is dispensable for general translation and cannot be considered as a functional translation initiation factor. 59,70 In a recent report, Liu and colleagues have investigated the role of DDX3 in HIV-1 translation in the context of a full-length provirus and with HIV-1 derived reporter genes.…”

Section: The Need For Additional Helicases In Hiv-1 Translationmentioning

confidence: 99%

Translation initiation of the HIV-1 mRNA

Ohlmann¹,

Mengardi²,

López-Lastra³

2014

translation

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Translation initiation of the full-length mRNA of the human immunodeficiency virus can occur via several different mechanisms to maintain production of viral structural proteins throughout the replication cycle. HIV-1 viral protein synthesis can occur by the use of both a capdependant and IRES-driven mechanism depending on the physiological conditions of the cell and the status of the ongoing infection. For both of these mechanisms there is a need for several viral and cellular co-factors for optimal translation of the viral mRNA. In this review we will describe the mechanism used by the full-length mRNA to initiate translation highlighting the role of co-factors within this process. A particular emphasis will be given to the role of the DDX3 RNA helicase in HIV-1 mRNA translation initiation.

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“…Numerous riboswitches undergo metabolite-induced changes in secondary and tertiary structures to regulate transcription or translation (Edwards et al 2007;Henkin 2008;Montange and Batey 2008;Wang and Breaker 2008). RNA conformational switching is also critical in the catalytic cycle of spliceosome-mediated premRNA splicing and during ribosome assembly, where specialized helicases assist in these processes (for reviews, see Le Hir and Andersen 2008;Tarn and Chang 2009). Aptamer modules adjacent to the hammerhead ribozyme catalytic core stabilize the active structures in otherwise disordered ribozymes upon binding of their respective ligands, and they can shift the base-pairing register of two strands to favor productive (or repressed) pairing interactions in the active site (Tang and Breaker 1997;Koizumi et al 1999;Soukup and Breaker 1999a;Win and Smolke 2008;Beisel and Smolke 2009;Win et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Assembly and activation of a kinase ribozyme

Burke

Rhee²

2010

RNA

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RNA activities can be regulated by modulating the relative energies of all conformations in a folding landscape; however, it is often unknown precisely how peripheral elements perturb the overall landscape in the absence of discrete alternative folds (inactive ensemble). This work explores the effects of sequence and secondary structure in governing kinase ribozyme activity. Kin.46 catalyzes thiophosphoryl transfer from ATPgS onto the 59 hydroxyl of polynucleotide substrates, and is regulated 10,000-fold by annealing an effector oligonucleotide to form activator helix P4. Transfer kinetics for an extensive series of ribozyme variants identified several dispensable internal single-stranded segments, in addition to a potential pseudoknot at the active site between segments J1/4 and J3/2 that is partially supported by compensatory rescue. Standard allosteric mechanisms were ruled out, such as formation of discrete repressive structures or docking P4 into the rest of the ribozyme via backbone 29 hydroxyls. Instead, P4 serves both to complete an important structural element (100-fold contribution to the reaction relative to a P4-deleted variant) and to mitigate nonspecific, inhibitory effects of the single-stranded tail (an additional 100-fold contribution to the apparent rate constant, k obs ). Thermodynamic activation parameters DH z and DS z , calculated from the temperature dependence of k obs , varied with tail length and sequence. Inhibitory effects of the unpaired tail are largely enthalpic for short tails and are both enthalpic and entropic for longer tails. These results refine the structural view of this kinase ribozyme and highlight the importance of nonspecific ensemble effects in conformational regulation by peripheral elements.

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The current understanding of Ded1p/DDX3 homologs from yeast to human

Cited by 85 publications

References 37 publications

DDX3 Regulates Cell Growth through Translational Control of Cyclin E1

DDX3 Regulates Cell Growth through Translational Control of Cyclin E1

Translation initiation of the HIV-1 mRNA

Assembly and activation of a kinase ribozyme

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