Steinberger et al. 2020 (PRJNA636959)
General Details
| Title | Authentication of Hippuristanol-eIF4A1 Target Engagement Facilitates Identification of eIF4A1 Helicase Dependencies within 5’ Leader Regions |
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| Organism | |
| Number of Samples | 6 |
| Release Date | 2020/06/03 00:00 |
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Study Links
| GWIPS-viz | Trips-Viz |
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Repository Details
| SRA | SRP265763 |
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| ENA | SRP265763 |
| GEO | GSE151687 |
| BioProject | PRJNA636959 |
Publication
| Title | |
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| Authors | Steinberger J, Shen L, J Kiniry S, Naineni SK, Cencic R, Amiri M, Aboushawareb SAE, Chu J, Maïga RI, Yachnin BJ, Robert F, Sonenberg N, Baranov PV, Pelletier J |
| Journal | Nucleic acids research |
| Publication Date | 2020 Sep 25 |
| Abstract | Hippuristanol (Hipp) is a natural product that selectively inhibits protein synthesis by targeting eukaryotic initiation factor (eIF) 4A, a DEAD-box RNA helicase required for ribosome recruitment to mRNA templates. Hipp binds to the carboxyl-terminal domain of eIF4A, locks it in a closed conformation, and inhibits its RNA binding. The dependencies of mRNAs for eIF4A during initiation is contingent on the degree of secondary structure within their 5' leader region. Interest in targeting eIF4A therapeutically in cancer and viral-infected settings stems from the dependencies that certain cellular (e.g. pro-oncogenic, pro-survival) and viral mRNAs show towards eIF4A. Using a CRISPR/Cas9-based variomics screen, we identify functional EIF4A1 Hipp-resistant alleles, which in turn allowed us to link the translation-inhibitory and cytotoxic properties of Hipp to eIF4A1 target engagement. Genome-wide translational profiling in the absence or presence of Hipp were undertaken and our validation studies provided insight into the structure-activity relationships of eIF4A-dependent mRNAs. We find that mRNA 5' leader length, overall secondary structure and cytosine content are defining features of Hipp-dependent mRNAs. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. |
| PMC | PMC7515738 |
| PMID | 32766783 |
| DOI |
| Run Accession | Study Accession | Scientific Name | Cell Line | Library Type | Treatment | GWIPS-viz | Trips-Viz | Reads | BAM | BigWig (F) | BigWig (R) | ||
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| SRR11915236 | PRJNA636959 | Homo sapiens | HAP1 | Ribo-Seq | Cycloheximide |  |
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| SRR11915237 | PRJNA636959 | Homo sapiens | HAP1 | Ribo-Seq | Cycloheximide | |
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| SRR11915238 | PRJNA636959 | Homo sapiens | HAP1 | Ribo-Seq | Cycloheximide | |
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| SRR11915239 | PRJNA636959 | Homo sapiens | HAP1 | Ribo-Seq | Cycloheximide | |
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| SRR11915240 | PRJNA636959 | Homo sapiens | HAP1 | Ribo-Seq | Cycloheximide | |
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| SRR11915241 | PRJNA636959 | Homo sapiens | HAP1 | Ribo-Seq | Cycloheximide | |
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| Run Accession | Study Accession | Scientific Name | Cell Line | Library Type | Treatment | GWIPS-viz | Trips-Viz | Reads | BAM | BigWig (F) | BigWig (R) |
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