A ribosomal pseudouridine drives an oncogenic translation program

Abstract

Ribosome heterogeneity can regulate translation, but how changes in ribosome chemistry reshape cellular programs and contribute to diseases such as cancer remains incompletely understood. Here we show that SNORA81-guided pseudouridylation at a single 28S ribosomal RNA site, U4636, links ribosome heterogeneity to selective translation and ovarian cancer cell proliferation. This partially modified site contacts eL31 near the peptide-exit region. SNORA81 depletion reduces U4636 pseudouridylation and changes ribosome occupancy in relation to codon identity and nascent-peptide properties without broadly disrupting rRNA processing or bulk polysome profiles. Depletion also redistributes mRNAs with distinct GC content and amino-acid composition across polysomes, with corresponding protein-abundance changes in selected cancer-associated targets. Wild-type SNORA81, but not a guide-region mutant, restores proliferation. Together, these findings support a “sno-balling” model in which altered abundance of a single snoRNA propagates through rRNA modification, selective ribosome engagement and protein output to reshape cancer-associated gene expression and cell behavior. Graphical Abstract The sno-balling effect links a single rRNA modification to cancer-associated translation. SNORA81-guided pseudouridylation at U4636 is associated with changes in ribosome occupancy, polysome association of compositionally distinct STAR mRNAs, and selected protein abundances. These findings support a model linking variation in rRNA modification to ovarian cancer cell proliferation.