RRC ID 56645
Author Iwasaki S, Floor SN, Ingolia NT.
Title Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor.
Journal Nature
Abstract Rocaglamide A (RocA) typifies a class of protein synthesis inhibitors that selectively kill aneuploid tumour cells and repress translation of specific messenger RNAs. RocA targets eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase; its messenger RNA selectivity is proposed to reflect highly structured 5' untranslated regions that depend strongly on eIF4A-mediated unwinding. However, rocaglate treatment may not phenocopy the loss of eIF4A activity, as these drugs actually increase the affinity between eIF4A and RNA. Here we show that secondary structure in 5' untranslated regions is only a minor determinant for RocA selectivity and that RocA does not repress translation by reducing eIF4A availability. Rather, in vitro and in cells, RocA specifically clamps eIF4A onto polypurine sequences in an ATP-independent manner. This artificially clamped eIF4A blocks 43S scanning, leading to premature, upstream translation initiation and reducing protein expression from transcripts bearing the RocA-eIF4A target sequence. In elucidating the mechanism of selective translation repression by this lead anti-cancer compound, we provide an example of a drug stabilizing sequence-selective RNA-protein interactions.
Volume 534(7608)
Pages 558-61
Published 2016-6-23
DOI 10.1038/nature17978
PII nature17978
PMID 27309803
PMC PMC4946961
MeSH 5' Untranslated Regions / genetics Adenosine Triphosphate / metabolism Benzofurans / pharmacology* DEAD-box RNA Helicases / chemistry DEAD-box RNA Helicases / metabolism Eukaryotic Initiation Factor-4A / chemistry Eukaryotic Initiation Factor-4A / metabolism* HEK293 Cells Humans Hydrolysis Nucleic Acid Conformation Nucleotide Motifs Open Reading Frames / genetics Peptide Chain Initiation, Translational / drug effects Protein Binding / drug effects Protein Biosynthesis / drug effects* Protein Stability / drug effects RNA, Messenger / chemistry RNA, Messenger / genetics* RNA, Messenger / metabolism* RNA-Binding Proteins / chemistry RNA-Binding Proteins / metabolism Repressor Proteins / chemistry Repressor Proteins / metabolism* Substrate Specificity / drug effects Thermodynamics
IF 43.07
Times Cited 85
DNA material pcDNA5/FRT/TO-SBP-eIF4A1 WT (RDB17295) pHISMBP-eIF4A1-NTD (WT) (RDB17304)