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.

Nature doi: 10.1038/nature17978

Nature Latest Research

 
STRATEGIES FOR A COMPANY’S INTELLECTUAL PROPERTY. IP protection is a part of your business strategy and matches your commercial goals. A simple IP strategy is to protect your product and service by getting patent, trademark and copyright certificates.
 

U.S. COMPANY REGISTRATION. We help our foreign clients with registering U.S. business to support moving their innovations to U.S. market. We assist in navigating the process of setting up a new business and support while it grows.

EXHIBITION PRESENTATION. We are working with major organizers of international conferences in USA. We discuss in advance all possible discounts and available places for your expositions.