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

eLife

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[1] Arbele Corporation, Seattle, United States;Department of Pathology, University of California, San Francisco, San Francisco, United States;Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, United States;Department of Pharmacology and Toxicology, Michigan State University, Grand Rapids, United States;Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States;Gladstone Histology and Light Microscopy Core, Gladstone Institutes, San Francisco, United States;Helen Diller Family Comprehensive Cancer Center and Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, United States;Helen Diller Family Comprehensive Cancer Center, Department of Medicine, University of California, San Francisco, San Francisco, United States;Helen Diller Family Comprehensive Cancer Center, Department of Urology, University of California, San Francisco, San Francisco, United States;Helen Diller Family Comprehensive Cancer Center, Department of Urology, University of California, San Francisco, San Francisco, United States;Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States;Helen Diller Family Comprehensive Cancer Center, Department of Urology, University of California, San Francisco, San Francisco, United States;Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, University of California, San Francisco, San Francisco, United States;

关键词: ribosome;    snoRNA;    pseudouridine modification;    steatohepatitic hepatocellular carcinoma;    translation;    noncoding RNA;    Human;    Mouse;   

DOI  :  10.7554/eLife.48847

来源: publisher

【 摘 要 】

10.7554/eLife.48847.001Small nucleolar RNAs (snoRNAs) are a diverse group of non-coding RNAs that direct chemical modifications at specific residues on other RNA molecules, primarily on ribosomal RNA (rRNA). SnoRNAs are altered in several cancers; however, their role in cell homeostasis as well as in cellular transformation remains poorly explored. Here, we show that specific subsets of snoRNAs are differentially regulated during the earliest cellular response to oncogenic RASG12V expression. We describe a novel function for one H/ACA snoRNA, SNORA24, which guides two pseudouridine modifications within the small ribosomal subunit, in RAS-induced senescence in vivo. We find that in mouse models, loss of Snora24 cooperates with RASG12V to promote the development of liver cancer that closely resembles human steatohepatitic hepatocellular carcinoma (HCC). From a clinical perspective, we further show that human HCCs with low SNORA24 expression display increased lipid content and are associated with poor patient survival. We next asked whether ribosomes lacking SNORA24-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 lacking SNORA24-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.

【 授权许可】

CC BY