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

doi:10.1016/j.celrep.2020.107611

Loss of m¹acp³Ψ Ribosomal RNA Modification Is a Major Feature of Cancer

Cell Rep. 2020 May 5;31(5):107611. doi: 10.1016/j.celrep.2020.107611.

Authors

Affiliations

¹ Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1 BC, Canada; Terry Fox Laboratory, BC Cancer, Vancouver, V5Z 1L3 BC, Canada. Electronic address: ababaian@bccrc.ca.
² Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1 BC, Canada; Terry Fox Laboratory, BC Cancer, Vancouver, V5Z 1L3 BC, Canada.
³ Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge, T1K 3M4 AB, Canada.
⁴ Max Delbrück Center for Molecular Medicine Berlin in the Helmholtz Association, Berlin Institute for Medical Systems Biology, Berlin 13125, Germany.
⁵ Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1 BC, Canada.
⁶ Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, V6H 3N1 BC, Canada.
⁷ 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.
⁸ 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.

PMID: 32375039
DOI: 10.1016/j.celrep.2020.107611

Abstract

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.

Keywords: RNA modification; cancer; colorectal carcinoma; diffuse large B-cell lymphoma; onco-ribosome; rRNA variation; ribosomal RNA; ribosomal heterogeneity; ribosome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence / genetics
Humans
Neoplasms / genetics*
Nucleic Acid Conformation
Oncogenes / genetics*
Pseudouridine / genetics
RNA, Ribosomal / metabolism*
Ribosomal Proteins / metabolism*
Ribosomes / metabolism*

Substances

RNA, Ribosomal
Ribosomal Proteins
Pseudouridine