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Disome profiling of rocaglamide A treatment in HEK293FT cells

ABSTRACT: For the past decade, extensive studies of translation have produced a vast amount of ribosome profiling data, an insightful resource for mining of critical details about the dynamics of translation regulation under various biological contexts. Previously, Rocaglamide A (RocA), an anti-tumor heterotricyclic natural compound, has been shown to selectively inhibit translation initiation of a large group of mRNA species by clamping eukaryotic translation initiation factor 4A (eIF4A) onto poly-purine motifs in the 5’ un-translational regions (5’UTRs). However, re-analysis of the previous ribosome profiling datasets revealed an unexpected shift of the ribosome occupancy pattern during early translation elongation upon RocA treatment in various types of cells, for a specific group of mRNA transcripts without poly-purine motifs over-presented in their 5’UTRs. Such perturbation of the translation elongation dynamics can be attributed to the blockage of translating ribosomes due to the binding of eIF4A to the poly-purine sequence in coding sequences. This new mode of action of RocA, which is complementary to the canonical function inhibiting translation initiation, selectively interfere with the translation of the genes involved in fundamental processes such as ATP synthase, mitochondrial respiratory chain complex, et al. In summary, re-analyses of previous ribosome profiling data has revealed the complete dual modes of RocA in blocking translation and thus underlying the potent anti-tumor effect

ORGANISM(S): Homo sapiens

PROVIDER: GSE201364 | GEO | 2022/12/17

REPOSITORIES: GEO

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Project description:DEAD-box RNA helicases eIF4A and Ded1 are believed to promote translation initiation by resolving mRNA secondary structures that impede ribosome attachment at the mRNA 5’ end or subsequent scanning of the 5’UTR, but whether they perform distinct functions or act redundantly in vivo is poorly understood. We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in yeast by ribosome footprint profiling. Despite similar reductions in bulk translation, inactivation of a cold-sensitive Ded1 mutant substantially reduced the TEs of >600 mRNAs, whereas inactivation of a temperature-sensitive eIF4A mutant yielded <40 similarly impaired mRNAs. The broader requirement for Ded1 did not reflect more pervasive secondary structures at low temperature, as inactivation of temperature-sensitive and cold-sensitive ded1 mutants gave highly correlated results. Interestingly, Ded1-dependent mRNAs exhibit greater than average 5’UTR length and propensity for secondary structure, implicating Ded1 in scanning though structured 5' UTRs. Reporter assays confirmed that cap- distal stem-loop insertions increase dependence on Ded1 but not eIF4A for efficient translation. While only a small fraction of mRNAs is strongly dependent on eIF4A, this dependence is significantly correlated with requirements for Ded1 and 5’UTR features characteristic of Ded1- dependent mRNAs. Our findings suggest that Ded1 is critically required to promote scanning through secondary structures within 5’UTRs; and while eIF4A cooperates with Ded1 in this function, it also promotes a step of initiation common to virtually all yeast mRNAs. We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in yeast by ribosome footprint profiling.The study includes 32 samples, comprised of 16 mRNA-Seq samples and 16 ribosome footprint profiling samples, derived from biological replicates of 3 mutant strains, ded1-cs, ded1-ts and tif1-ts, and the corresponding wild-type strains. The tif1-ts mutant and its wild-type counterpart were analyzed at 30°C and 37°C.

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Disome profiling of rocaglamide A treatment in HEK293FT cells

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