Unwinding Single RNA Molecules Using Helicases Involved in Eukaryotic Translation Initiation

Marsden, Steven; Nardelli, Maria; Linder, Patrick; McCarthy, John E.G.

doi:10.1016/j.jmb.2006.06.016

Cited by 66 publications

(72 citation statements)

References 27 publications

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“…7 Subsequent biochemical studies further showed that Ded1p can modulate RNA unwinding 11,12 and strand annealing, 12 and is likely to act as a more potent unwinding factor than eIF4A to assist 40S ribosomal subunit in scanning for the AUG codon. 13 In this regard, our recent data (Chang T-H, unpublished) are also consistent with the idea that Ded1p plays an early role in translation initiation.…”

Section: Role Of the Yeast Ded1p In Translationsupporting

confidence: 86%

“…13,35 Perhaps eIF4A functions to loosen local imperfect pairing in the 5'UTR, whereas Ded1p/ DDX3 acts to resolve stronger RNA structures or to remodel RNP complexes within the 5'UTR by virtue of its more powerful unwindase activity. 13 The effect of excess DDX3 in translation. While DDX3's role in global translation remains debatable, its overexpression was reported to inhibit translation in vivo.…”

Section: Discussionmentioning

confidence: 99%

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

Tarn¹

2009

RNA Biology

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Section: Role Of the Yeast Ded1p In Translationsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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

Tarn¹

2009

RNA Biology

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“…5 and 6). Biochemical studies have indicated that yeast Ded1 is more potent than eIF4A with regard to RNA unwinding activity, and therefore Ded1 may enable the 40S ribosomal subunit to achieve higher processivity while scanning for the initiation codon (3,32). DDX3 may likewise participate in such a step.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 96%

DDX3 Regulates Cell Growth through Translational Control of Cyclin E1

Lai

Chang

Shieh

et al. 2010

Molecular and Cellular Biology

160

178

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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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“…There is evidence that Ded1p is required (in addition to the DEAD-box containing translation initation factor eIF4a) for the unwinding of 5' untranslated regions (UTRs), with Ded1p being faster and more efficient in the scanning of long 5'UTRs than eIF4a [25,26]. It was shown that human DDX3 can substitute for Ded1p in genetic complementation studies, suggesting that the human protein also facilitates translation initiation.…”

Section: Protein Translationmentioning

confidence: 99%

Human DEAD-box protein 3 has multiple functions in gene regulation and cell cycle control and is a prime target for viral manipulation

Schröder

2010

Biochemical Pharmacology

127

128

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To cite this version:Martina Schröder. Human DEAD-box protein 3 has multiple functions in gene regulation and cell cycle control and is a prime target for viral manipulation. Biochemical Pharmacology, Elsevier, 2009, 79 (3) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 42A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 AbstractThe human DEAD-box RNA helicase DDX3 has been implicated to play a role in the whole repertoire of processes regulating gene expression, including transcription, splicing, mRNA export and translation. It has also been suggested to be involved in cell cycle control and the regulation of apoptosis. In addition, DDX3 was recently shown to be part of innate immune signalling pathways and to contribute to the induction of anti-viral mediators, such as type I interferon. Interestingly, DDX3 appears to be a prime target for viral manipulation: at least four different viruses, namely Hepatitis C virus (HCV), Hepatitis B virus (HBV), Human immunodeficiency virus (HIV) and poxviruses, encode proteins that interact with DDX3 and modulate its function. HIV and HCV seem to co-opt DDX3 and require it for their replication. It has therefore been suggested that DDX3 could be a novel target for the development of drugs against these two viruses, both of which still pose major global health threats. However, in the light of the apparent multifunctionality of DDX3 in the cell, drug development strategies targeting DDX3 will have to be carefully evaluated. This review summarises the available data on the cellular functions of DDX3 and discusses their manipulation by the different viruses known to target DDX3. Understanding the viral strategies for manipulating or co-opting DDX3 in functional and molecular detail can provide valuable insights for the development of strategies to therapeutically target DDX3.

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Unwinding Single RNA Molecules Using Helicases Involved in Eukaryotic Translation Initiation

Cited by 66 publications

References 27 publications

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

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

DDX3 Regulates Cell Growth through Translational Control of Cyclin E1

Human DEAD-box protein 3 has multiple functions in gene regulation and cell cycle control and is a prime target for viral manipulation

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