Translatome and translation dynamics analysis of a RiboCancer cell line panel reveals that leukemia-associated Rps15 mutations rewire translation through codon-specific tRNA accommodation defects

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ABSTRACT Deletions and point mutations targeting ribosomal proteins (RPs) have been identified in cancer. Yet, their role in translational dysregulation remains poorly understood. We performed an integrated genome-wide translatome analysis (proteome, Ribo-seq and total RNA-seq) as well as RiboMethSeq on an isogenic cell line library modeling the most recurrent RP defects in cancer (Rpl5 +/− , Rpl11 +/− , Rpl22 +/− , Rpl22 −/− , Rpl10 R98S, Rps15 P131S and Rps15 H137Y). RP knock-out had minimal effects on translation, whereas RP point mutations induced a significant number of translation efficiency changes, affecting up to 10% of expressed genes in Rps15 mutants associated with Chronic Lymphocytic Leukemia (CLL). Cryo-electron microscopy and biochemical analyses revealed that the Rps15 mutations destabilize the C-terminal Rps15 domain, affecting the translation elongation cycle dynamics, and deregulating accommodation of aminoacylated tRNAs at the ribosomal A-site. Using Ribo-seq and translation reporter assays, we show that this accommodation defect shows codon specificity, explaining the reduced translation efficiency of genes enriched for these codons in Rps15 mutant cells, such as histones. Notably, genes with reduced translation efficiency in Rps15 mutated cells were enriched for transcriptional regulators such as transcription factor Runx3, resulting in downregulation of Runx3 target genes involved in immune regulation. Altogether, this study provides a comparative map of the translational rewiring driven by the most frequent somatic RP mutations. We provide unprecedented mechanistic insights in the translation defects induced by CLL-associated Rps15 mutations, and reveal an unappreciated cross-talk between translational and transcriptional dysregulation in these RP mutant cells. GRAPHICAL ABSTRACT

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