Loss of m1acp3Ψ Ribosomal RNA Modification Is a Major Feature of Cancer
Artem Babaian,
Katharina Rothe,
Dylan Girodat,
Igor Minia,
Sara Djondovic,
Miha Milek,
Sandra E. Spencer Miko,
Hans-Joachim Wieden,
Markus Landthaler,
Gregg B. Morin,
Dixie L. Mager
Affiliations
Artem Babaian
Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1 BC, Canada; Terry Fox Laboratory, BC Cancer, Vancouver, V5Z 1L3 BC, Canada; Corresponding author
Katharina Rothe
Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1 BC, Canada; Terry Fox Laboratory, BC Cancer, Vancouver, V5Z 1L3 BC, Canada
Dylan Girodat
Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge, T1K 3M4 AB, Canada
Igor Minia
Max Delbrück Center for Molecular Medicine Berlin in the Helmholtz Association, Berlin Institute for Medical Systems Biology, Berlin 13125, Germany
Sara Djondovic
Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1 BC, Canada
Miha Milek
Max Delbrück Center for Molecular Medicine Berlin in the Helmholtz Association, Berlin Institute for Medical Systems Biology, Berlin 13125, Germany
Sandra E. Spencer Miko
Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, V6H 3N1 BC, Canada
Hans-Joachim Wieden
Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge, T1K 3M4 AB, Canada
Markus Landthaler
Max Delbrück Center for Molecular Medicine Berlin in the Helmholtz Association, Berlin Institute for Medical Systems Biology, Berlin 13125, Germany; IRI Life Sciences, Institut für Biologie, Humboldt Universität, Berlin 10115, Germany
Gregg B. Morin
Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1 BC, Canada; Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, V6H 3N1 BC, Canada
Dixie L. Mager
Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1 BC, Canada; Terry Fox Laboratory, BC Cancer, Vancouver, V5Z 1L3 BC, Canada
Summary: 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.U 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-α-amino-α-carboxyl-propyl pseudouridine (m1acp3Ψ), a >1-billion-years-conserved RNA modification at the peptidyl decoding site of the ribosome. A subset of CRC tumors we call hypo-m1acp3Ψ shows sub-stoichiometric m1acp3Ψ modification, unlike normal control tissues. An m1acp3Ψ knockout model and hypo-m1acp3Ψ patient tumors share a translational signature characterized by highly abundant ribosomal proteins. Thus, m1acp3Ψ-deficient rRNA forms an uncharacterized class of “onco-ribosome” which may serve as a chemotherapeutic target for treating cancer patients.
