A ribosomal pseudouridine drives an oncogenic translation program

Dynamic ribosome heterogeneity has emerged as a potential layer of translational regulation, but whether variation in ribosomal RNA (rRNA) modification stoichiometry can selectively control the translation of mRNAs with shared encoded features remains unclear. Here we show that SNORA81-guided pseudouridylation at U4636 controls a selective translational program in ovarian cancer cells. U4636 is partially pseudouridylated and lies within 28S rRNA near eL31 and the peptide exit tunnel. Depletion of SNORA81 reduces pseudouridylation at U4636 without broadly perturbing rRNA processing or bulk translation. Instead, it remodels codon-specific and nascent-peptide-associated pausing and the polysome association of SNORA81-dependent translationally altered mRNAs. These mRNAs display characteristic GC content and amino-acid composition, are enriched in cancer-related functions and show corresponding changes in protein levels. Our findings support a model in which a change in the abundance of a single snoRNA propagates from rRNA-modification stoichiometry through ribosome dynamics and selective mRNA translation to protein output and cancer cell proliferation. We term this multilevel amplification cascade the "sno-balling" effect.