A single H/ACA small nucleolar RNA mediates tumor suppression downstream of oncogenic RAS

We describe a novel function for one H/ACA snoRNA,SNORA24, which guides two pseudouridine modifications within the small ribosomal subunit, in RAS-induced senescencein vivo. We find that in mouse models, loss ofSnora24 cooperates with RASG12V to promote the development of liver cancer that closely resembles human steatohepatitic hepatocellular carcinoma. From a clinical perspective, we further show that human hepatocellular carcinomas with lowSNORA24 expression display increased lipid content and are associated with poor patient survival. We next asked whether ribosomes lackingSNORA24-guided pseudouridine modifications on 18S rRNA have alterations in their biophysical properties. Single-molecule Fluorescence Resonance Energy Transfer (FRET) analyses revealed that these ribosomes exhibit perturbations in aminoacyl-transfer RNA (aa-tRNA) selection and altered pre-translocation ribosome complex dynamics. Furthermore, we find that HCC cells lackingSNORA24-guided pseudouridine modifications have increased translational miscoding and stop codon readthrough frequencies. These findings highlight a role for specific snoRNAs in safeguarding against oncogenic insult and demonstrate a functional link between H/ACA snoRNAs regulated by RAS and the biophysical properties of ribosomes in cancer.
Source: eLife - Category: Biomedical Science Tags: Cancer Biology Chromosomes and Gene Expression Source Type: research