DDX3 Activates CBC-eIF3–Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC

Chen, Hung Hsi; Yu, Hsin I.; Yang, Muh Hwa; Tarn, Woan Yuh

doi:10.1158/0008-5472.can-18-0282

Cited by 67 publications

(77 citation statements)

References 49 publications

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“…However, other reporter RNAs, such as ATF5, CCNE1, and RPLP1, did not change in the in vitro translation upon DDX3 knockdown ( Figure 1F). RPLP1 was identified as an mRNA with uORF occupancy changes upon mutant DDX3 expression in prior work (Oh et al 2016), while ATF5 and CCNE1 were previously implicated in DDX3dependent translation (Lai et al 2010;Chen et al 2018).…”

Section: Identifying Mrnas That Depend On Ddx3 For Efficient Translationmentioning

confidence: 99%

DDX3 depletion represses translation of mRNAs with complex 5′ UTRs

Venkataramanan

Rogowski

Wyler

et al. 2019

Preprint

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DDX3 is an RNA chaperone of the DEAD-box family that regulates translation. Its yeast ortholog Ded1 controls the translation of nearly all mRNAs, whereas DDX3 is thought to regulate only a subset of mRNAs. However, the set of mRNAs that are regulated by DDX3 are unknown, along with the relationship between DDX3 binding and activity. Here, we use ribosome profiling, RNA-seq, and PAR-CLIP to define the set of mRNAs that are regulated by DDX3 in human cells. We find that while DDX3 binds most expressed mRNAs, depletion of DDX3 affects the translation level of only a small subset of the transcriptome. We further find that DDX3 binds a site on helix 16 of the human ribosome, placing it immediately adjacent to the mRNA entry channel and translation factor eIF4B. Translation changes caused by depleting DDX3 levels or through chemical inhibition mimicking a dominant negative allele are different. Taken together, our data defines the subset of the transcriptome that is responsive to DDX3 inhibition, with relevance for basic biology and disease states where DDX3 expression is altered.

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Section: Identifying Mrnas That Depend On Ddx3 For Efficient Translationmentioning

confidence: 99%

DDX3 depletion represses translation of mRNAs with complex 5′ UTRs

Venkataramanan

Rogowski

Wyler

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…In head and neck squamous cell carcinoma, DDX3 promotes the association of the cap-binding complex with mRNAs and enhances recruitment of EIF3, thereby contributing to the expression of metastatic-related gene expression [108].…”

Section: Eif3mentioning

confidence: 99%

Functions of N6-methyladenosine and its role in cancer

et al. 2019

Mol Cancer

859

816

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N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.

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“…manuscript in preparation). It was recently reported that the DEAD-box RNA helicase DDX3, which is critical for nuclear export and translation of the HIV-1 unspliced mRNA ( 38 , 42 , 44 , 68 ), promotes CBC-eIF3-mediated translation ( 69 ). These observations suggest that CBP80 (probably with Rev, eIF4A and DDX3) might promote Gag synthesis in the context of a non-canonical CBC that mediates the recruitment of the 40S ribosomal subunit.…”

Section: Discussionmentioning

confidence: 99%

A Rev–CBP80–eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA

Toro-Ascuy

Rojas-Araya

García-de-Gracia

et al. 2018

Nucleic Acids Research

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Gag synthesis from the full-length unspliced mRNA is critical for the production of the viral progeny during human immunodeficiency virus type-1 (HIV-1) replication. While most spliced mRNAs follow the canonical gene expression pathway in which the recruitment of the nuclear cap-binding complex (CBC) and the exon junction complex (EJC) largely stimulates the rates of nuclear export and translation, the unspliced mRNA relies on the viral protein Rev to reach the cytoplasm and recruit the host translational machinery. Here, we confirm that Rev ensures high levels of Gag synthesis by driving nuclear export and translation of the unspliced mRNA. These functions of Rev are supported by the CBC subunit CBP80, which binds Rev and the unspliced mRNA in the nucleus and the cytoplasm. We also demonstrate that Rev interacts with the DEAD-box RNA helicase eIF4AI, which translocates to the nucleus and cooperates with the viral protein to promote Gag synthesis. Finally, we show that the Rev/RRE axis is important for the assembly of a CBP80-eIF4AI complex onto the unspliced mRNA. Together, our results provide further evidence towards the understanding of the molecular mechanisms by which Rev drives Gag synthesis from the unspliced mRNA during HIV-1 replication.

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DDX3 Activates CBC-eIF3–Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC

Cited by 67 publications

References 49 publications

DDX3 depletion represses translation of mRNAs with complex 5′ UTRs

DDX3 depletion represses translation of mRNAs with complex 5′ UTRs

Functions of N6-methyladenosine and its role in cancer

A Rev–CBP80–eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA

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