Oliver et al. 2020 (PRJNA412370)
General Details
| Title | Ribosomal coverage with codon resulation in response to RPL12 siRNA treatment vs. no treatment |
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| Organism | |
| Number of Samples | 4 |
| Release Date | 2017/09/27 00:00 |
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| Protocol Details |
Study Links
| GWIPS-viz | Trips-Viz |
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Repository Details
| SRA | SRP118987 |
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| ENA | SRP118987 |
| GEO | GSE104329 |
| BioProject | PRJNA412370 |
Publication
| Title | |
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| Authors | Oliver KE, Rauscher R, Mijnders M, Wang W, Wolpert MJ, Maya J, Sabusap CM, Kesterson RA, Kirk KL, Rab A, Braakman I, Hong JS, Hartman JL 4th, Ignatova Z, Sorscher EJ |
| Journal | The Journal of clinical investigation |
| Publication Date | 2019 Dec 2 |
| Abstract | Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), with approximately 90% of patients harboring at least one copy of the disease-associated variant F508del. We utilized a yeast phenomic system to identify genetic modifiers of F508del-CFTR biogenesis, from which ribosomal protein L12 (RPL12/uL11) emerged as a molecular target. In the present study, we investigated mechanism(s) by which suppression of RPL12 rescues F508del protein synthesis and activity. Using ribosome profiling, we found that rates of translation initiation and elongation were markedly slowed by RPL12 silencing. However, proteolytic stability and patch-clamp assays revealed RPL12 depletion significantly increased F508del-CFTR steady-state expression, interdomain assembly, and baseline open-channel probability. We next evaluated whether Rpl12-corrected F508del-CFTR could be further enhanced with concomitant pharmacologic repair (e.g., using clinically approved modulators lumacaftor and tezacaftor) and demonstrated additivity of these treatments. Rpl12 knockdown also partially restored maturation of specific CFTR variants in addition to F508del, and WT Cftr biogenesis was enhanced in the pancreas, colon, and ileum of Rpl12 haplosufficient mice. Modulation of ribosome velocity therefore represents a robust method for understanding both CF pathogenesis and therapeutic response. |
| PMC | PMC6877332 |
| PMID | 31657788 |
| 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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| SRR6107148 | PRJNA412370 | Homo sapiens | CFBE | Ribo-Seq | Harringtonine |  |
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| SRR6107149 | PRJNA412370 | Homo sapiens | CFBE | Ribo-Seq | Cycloheximide | |
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| SRR6107150 | PRJNA412370 | Homo sapiens | CFBE | Ribo-Seq | Cycloheximide | |
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| SRR6107151 | PRJNA412370 | Homo sapiens | CFBE | 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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