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SRX5250476: GSM3562582: Vehicle-treated, replicate A footprints; Homo sapiens; OTHER
1 ILLUMINA (Illumina HiSeq 2500) run: 15.6M spots, 782.3M bases, 345.2Mb downloads

Submitted by: NCBI (GEO)
Study: Ribosome queuing enables non-AUG translation to be resistant to multiple protein synthesis inhibitors
show Abstracthide Abstract
Aberrant translation initiation at non-AUG start codons is associated with multiple cancers and neurodegenerative diseases. Nevertheless, how non-AUG translation is regulated differently from canonical translation is poorly understood. We thus used start codon-selective reporters and ribosome profiling to characterize how translation from non-AUG start codons responds to protein synthesis inhibitors in human cells. These analyses surprisingly revealed that translation of non-AUG reporters and the endogenous GUG-encoded DAP5 (eIF4G2/p97) mRNA are resistant to cycloheximide (CHX), a translation inhibitor which slows but does not completely abrogate elongation. Our data suggest that slowly elongating ribosomes cause queuing of scanning pre-initiation complexes (PIC), preferentially enhancing otherwise poor recognition of non-AUG start codons. Consistent with this model, limiting PIC formation or scanning sensitizes non-AUG translation to CHX. Moreover, PIC queuing can cause translation from an AUG codon in a poor context to become less sensitive to CHX. We further find that non-AUG translation is resistant to other inhibitors that target ribosomes within the coding sequence, but not those targeting newly initiated ribosomes. In total, these data indicate that ribosome queuing enables mRNAs with poor initiation context, namely those from non-AUG start codons, to be resistant to pharmacological inhibitors. Overall design: Measuring translational efficiency genome-wide in response to prolonged cyclohexamide treatment
Sample: Vehicle-treated, replicate A footprints
SAMN10743996 • SRS4252124 • All experiments • All runs
Organism: Homo sapiens
Library:
Instrument: Illumina HiSeq 2500
Strategy: OTHER
Source: TRANSCRIPTOMIC
Selection: other
Layout: SINGLE
Construction protocol: At each time point, cells were placed on ice, washed with 10 mL ice-cold PBS with 100 μg/mL CHX, and lysed in plate in 400 uL of cold lysis buffer (20 mM Tris, pH.4; 150 mM NaCl; 5 mM MgCl2; 1 mM DTT; 1% Triton X-100; 50 μg/mL emetine; 25 U/mLTurbo DNase [Thermo Fisher Scientific]). Cells were then scraped off the plate, transferred to a 1.5 mL tube, and incubated on ice for 5 min. Cell debris was pelleted at 16,000 x g for 10 min at 4°C. The resulting supernatant was then snap frozen in liquid nitrogen before storing at -80°C. Ribosome profiling was performed as previously described (Ingolia et al. 2012) with minor modifications. Briefly, cell lysates were thawed, treated with RNase I, and then pelleted over a 1 M sucrose cushion containing 100 μg/mL emetine. RNA was then size-selected by excising between the 15 and 34 nt marker oligonucleotides, and ligated to the Universal miRNA Cloning Linker (NEB). rRNA depletion was then performed using the RiboZero rRNA Removal Kit (Human version, Illumina), followed by reverse transcription, circularization, and PCR amplification. For RNA-seq, total RNA was extracted from thawed cell lysates. Libraries were then made from 0.3 μg of total RNA using the TruSeq Stranded Total RNA kit (Illumina) according to the manufacturer's instructions, and amplified by PCR for 10 cycles. All libraries were sequenced on a HiSeq 2500 system at the Genetic Resource Core Facility of the Johns Hopkins University School of Medicine
Experiment attributes:
GEO Accession: GSM3562582
Links:
Runs: 1 run, 15.6M spots, 782.3M bases, 345.2Mb
Run# of Spots# of BasesSizePublished
SRR844330815,646,219782.3M345.2Mb2019-06-05

ID:
7086542

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