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Rules governing translation selectivity under limiting ribosome availability

ABSTRACT: Ribosomopathies are cell-type-specific pathologies related to a ribosomal protein (RP) gene insult. The 5q- syndrome is a somatic ribosomopathy linked to RPS14 gene haploinsufficiency and characterized by a prominent erythroid hypoplasia. Using quantitative proteomic, we show that GATA1 protein expression is low in shRPS14 cells in which ribosome quantities are diminished. Here, we investigated the cause of low GATA1 protein expression in limiting ribosome availability. A global analysis of translation in RPs deficiencies highlights the rules that drive translation selectivity. We demonstrate that in addition of the transcript length, a high codon adaptation index (CAI) and a highly structured 3’UTR are the key characteristics for a selective translation. An integrated analysis of transcriptome and proteome confirms that the post-transcriptional regulations of gene expression are directly linked to the criteria governing the translational selectivity. In particular, these criteria explain GATA1 translation default with unprecedented precision. More generally, the proteins that accumulate along normal erythropoiesis share the determinants of translation selectivity revealed by the conditions of limiting ribosome availability. We performed translatome expression profiling of cells infected with shRPS14 or shSCR

ORGANISM(S): Homo sapiens

PROVIDER: GSE124800 | GEO | 2020/04/28

REPOSITORIES: GEO

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mRNA length and 3’UTR structure govern the translation selectivity in RPS14-haploinsufficient erythroblasts

Project description:5q- syndrome is a somatic ribosomopathy linked to the monoallelic deletion of the RPS14 gene and characterized by a proeminent erythroid phenotype. The mechanism of anemia involves an impaired differentiation and increased apoptosis of erythroblasts. We have analyzed total cell extracts from UT7 cells with or without a decrease of RPS14 proteins induced by shRNAs. Our data show that GATA1 protein expression is low in line with a defect in the representation of its mRNA at the ribosome. A global analysis of transcripts on polysomes indicates that translation is selective with a decreased representation of the transcripts with a short coding sequence and UTRs and a highly structured 3’UTR, a subset of transcripts that includes GATA1. Our whole proteome analysis confirms that post-transcriptionally downregulated proteins were encoded by transcripts with a short length and structured 3’UTR. We identified a subset of post-translationally downregulated proteins including ribosomal proteins and translation elongation factors encoded by 5’TOP mRNAs that were enriched on the ribosome. Our results indicate that the thermodynamic characteristics of 3’UTR and in a lesser extend 5’UTR and the transcript length are the determinants of translation selectivity under RPS14 haploinsufficiency conditions and that a post-translational regulation of ribosomal proteins accounts for their decreased content in the cell.

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Rules governing translation selectivity under limiting ribosome availability

Project description:Rules governing translation selectivity under limiting ribosome availability

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mRNA length and 3’UTR structure govern the translation selectivity in RPS14-haploinsufficient erythroblasts [translatome]

Project description:5q- syndrome is a somatic ribosomopathy linked to the monoallelic deletion of the RPS14 gene and characterized by a proeminent erythroid phenotype. The mechanism of anemia involves an impaired differentiation and increased apoptosis of erythroblasts. Here we show that GATA1 protein expression is low in line with a defect in the representation of its mRNA at the ribosome. A global analysis of transcripts on polysomes indicates that translation is selective with a decreased representation of the transcripts with a short coding sequence and UTRs and a highly structured 3’UTR, a subset of transcripts that includes GATA1. Our whole proteome analysis confirms that post-transcriptionally downregulated proteins were encoded by transcripts with a short length and structured 3’UTR. We identified a subset of post-translationally downregulated proteins including ribosomal proteins and translation elongation factors encoded by 5’TOP mRNAs that were enriched on the ribosome. Our results indicate that the thermodynamic characteristics of 3’UTR and in a lesser extend 5’UTR and the transcript length are the determinants of translation selectivity under RPS14 haploinsufficiency conditions and that a post-translational regulation of ribosomal proteins accounts for their decreased content in the cell. We performed transcriptome and translatome expression profiling of cells infected with shRPS14 or shSCR

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Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor

Project description:Rocaglamide A (RocA) typifies a class of protein synthesis inhibitors that selectively kill aneuploid tumor cells and repress translation of specific mRNAs. RocA targets eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase; its mRNA selectivity is proposed to reflect highly structured 5â² UTRs 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 5â² UTRs is only a minor determinant for RocA selectivity and 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. Bind-n-Seq and iCLIP-Seq

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