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Series GSE108334 Query DataSets for GSE108334
Status Public on Dec 21, 2017
Title eIF1A residues implicated in cancer stabilize translation preinitiation complexes and favor suboptimal initiation sites in yeast
Organism Saccharomyces cerevisiae
Experiment type Expression profiling by high throughput sequencing
Summary The translation pre-initiation complex (PIC) scans the mRNA for an AUG codon in favorable context, and AUG recognition stabilizes a closed PIC conformation. The unstructured N-terminal tail (NTT) of yeast eIF1A deploys five basic residues to contact tRNAi, mRNA, or 18S rRNA exclusively in the closed state. Interestingly, EIF1AX mutations altering the human eIF1A NTT are associated with uveal melanoma (UM). We found that substituting all five basic residues, and seven UM-associated substitutions, in yeast eIF1A suppresses initiation at near-cognate UUG codons and AUGs in poor context. Ribosome profiling of NTT substitution R13P reveals heightened discrimination against unfavorable AUG context genome-wide. Both R13P and K16D substitutions destabilize the closed complex at UUG codons in reconstituted PICs. Thus, electrostatic interactions involving the eIF1A NTT stabilize the closed conformation and promote utilization of suboptimal start codons. We predict UM-associated mutations alter human gene expression by increasing discrimination against poor initiation sites.
Overall design We examined the effect of tif11-R13P on global translational efficiencies (TEs) by ribosome footprint profiling of isogenic WT and tif11-R13P strains. The study includes 8 samples, comprised of 4 mRNA-Seq samples and 4 ribosome footprint profiling samples, derived from 2 biological replicates of tif11? mutant strains harboring plasmid-borne tif11-R13P or the WT TIF11 allele. Additional Ribosome profiling data were used for yeast uORF identification.
Contributor(s) Martin-Marcos P, Zhou F, Karunasiri C, Zhang F, Dong J, Nanda J, Shardul KD, Sen N, Tamame M, Zeschnigk M, Lorsch JR, Hinnebusch AG
Citation(s) 29206102
Submission date Dec 20, 2017
Last update date Mar 11, 2019
Contact name Jon R. Lorsch
Phone 301-594-2172
Organization name National Institutes of Health
Department Eunice Kennedy Shriver National Institute of Child Health and Human Development,
Lab Section on the Mechanism and Regulation of Protein Synthesis
Street address BG 49 RM 2C08, 49 Convent Dr.
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
Platforms (1)
GPL17342 Illumina HiSeq 2500 (Saccharomyces cerevisiae)
Samples (48)
GSM2895444 mRNA_TIF11_R13P_1
GSM2895445 mRNA_TIF11_R13P_2
GSM2895446 mRNA_WT(for TIF11_R13P)_1
BioProject PRJNA423281
SRA SRP127274

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Supplementary file Size Download File type/resource
GSE108334_Dataset-list.pdf 110.9 Kb (ftp)(http) PDF
GSE108334_Yeast_Strain_Genotypes.pdf 160.1 Kb (ftp)(http) PDF
GSE108334_all_uorf_info.xlsx.gz 349.3 Kb (ftp)(http) XLSX
GSE108334_mrna-TIF11_fwd.wig.gz 4.1 Mb (ftp)(http) WIG
GSE108334_mrna-TIF11_rev.wig.gz 3.4 Mb (ftp)(http) WIG
GSE108334_mrna-tif11-R13P_fwd.wig.gz 3.4 Mb (ftp)(http) WIG
GSE108334_mrna-tif11-R13P_rev.wig.gz 3.2 Mb (ftp)(http) WIG
GSE108334_ribo_TIF11_fwd.wig.gz 3.9 Mb (ftp)(http) WIG
GSE108334_ribo_TIF11_rev.wig.gz 3.8 Mb (ftp)(http) WIG
GSE108334_ribo_tif11-R13P_fwd.wig.gz 3.5 Mb (ftp)(http) WIG
GSE108334_ribo_tif11-R13P_rev.wig.gz 3.4 Mb (ftp)(http) WIG
GSE108334_yeast_all_uorfs.bed.gz 86.7 Kb (ftp)(http) BED
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