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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Blood Cell, Permanent Cell Line Cell, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Emilie-Fleur GAUTIER  

LAB HEAD: Patrick MAYEUX

PROVIDER: PXD008650 | Pride | 2021-04-28

REPOSITORIES: Pride