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| Status |
Public on Jul 18, 2020 |
| Title |
Master stress response gene ATF4 & other oncogenes are translated by DENR-dependent reinitiation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Other
|
| Summary |
Translation efficiency varies 1000-fold between different mRNAs, thereby strongly impacting protein expression. Translation of the master stress response gene ATF4 increases in response to stress, but the molecular mechanisms are not well understood. We discover here that translation initiation factors DENR, MCTS1 and eIF2D are absolutely required to induce ATF4 translation upon stress, by promoting translation reinitiation on the ATF4 5’UTR. Hence DENR and MCTS1 are important players in the cellular Integrated Stress Response. We find DENR and MCTS1 promote reinitiation after long uORFs with specific penultimate codons, due to the tRNA that remains attached to 40S ribosomes after translation termination. This provides a model for how DENR and MCTS1 promote translation reinitiation. Since cancer cells are exposed to many stresses, they require ATF4 for survival and proliferation. We find a strong correlation between DENR•MCTS1 expression and ATF4 activity across cancers. Additional oncogenes including a-Raf, c-Raf and Cdk4 have long uORFs and are translated in a DENR•MCTS1 dependent manner. This explains in part why DENR and MCTS1 are oncogenes.
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| Overall design |
We created a DENR KO Hela Cell line and carried out ribosome footprinting to determine translational targets of the DENR-MCTS1 complex.
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| Contributor(s) |
Bohlen J, Teleman A |
| Citation(s) |
32938922 |
| |
| Submission date |
Nov 07, 2019 |
| Last update date |
Sep 24, 2020 |
| Contact name |
Jonathan Bohlen |
| Organization name |
DKFZ
|
| Department |
B140
|
| Lab |
AG Teleman
|
| Street address |
Im Neuenheimer Feld 581
|
| City |
Heidelberg |
| ZIP/Postal code |
69123 |
| Country |
Germany |
| |
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| Platforms (1) |
|
| Samples (9)
|
| GSM4154182 |
80S Ribosome Footprints from WT Hela Cells |
| GSM4154183 |
80S Ribosome Footprints from DENR KO Hela Cell Line 1 |
| GSM4154184 |
80S Ribosome Footprints from DENR KO Hela Cell Line 2 |
| GSM4154185 |
RNA-seq from WT Hela Cells |
| GSM4154186 |
RNA-seq from DENR KO Hela Cell Line 1 |
| GSM4154187 |
RNA-seq from DENR KO Hela Cell Line 2 |
| GSM4478779 |
40S Ribosome Footprints from WT Hela Cells |
| GSM4478780 |
40S Ribosome Footprints from DENR KO Hela Cell Line 1 |
| GSM4478781 |
40S Ribosome Footprints from DENR KO Hela Cell Line 2 |
|
| Relations |
| BioProject |
PRJNA588223 |
| SRA |
SRP229088 |
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