Journal
CELL REPORTS
Volume 31, Issue 5, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.107611
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Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Leukemia and Lymphoma Society of Canada
- NSERC Alexander Graham Bell Graduate Scholarship
- Roman Babicki Fellowship in Medical Research from the University of British Columbia
- Amazon Web Services (AWS)
- Mathematics of Information Technology and Complex Systems (MITACS) Elevate Postdoctoral Fellowship
- Alberta Innovates (Technology Futures) Graduate Student Scholarship
- Alberta Innovates (Strategic Chairs Program) [SC60-T2]
- NSERC Discovery Grant [RGPIN-2016-05199]
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The ribosome is an RNA-protein complex that is essential for translation in all domains of life. The structural and catalytic core of the ribosome is its ribosomal RNA (rRNA). While mutations in ribosomal protein (RP) genes are known drivers of oncogenesis, oncogenic rRNA variants have remained elusive. We identify a cancer-specific single-nucleotide variation in 18S rRNA at nucleotide 1248.0 in up to 45.9% of patients with colorectal carcinoma (CRC) and present across >22 cancer types. This is the site of a unique hyper-modified base, 1-methyl-3-alpha-amino-alpha-carboxyl-propyl pseudouridine (m(1)acp(3)Psi), a >1-billion-years-conserved RNA modification at the peptidyl decoding site of the ribosome. A subset of CRC tumors we call hypo m(1)acp(3)Psi, shows sub-stoichiometric m(1)acp(3)Psi modification, unlike normal control tissues. An m(1)acp(3)Psi knockout model and hypo-m(1)acp(3)Psi, patient tumors share a translational signature characterized by highly abundant ribosomal proteins. Thus, m(1)acp(3)Psi-deficient rRNA forms an uncharacterized class of onco-ribosome which may serve as a chemotherapeutic target for treating cancer patients.
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