Loss of macpΨ ribosomal RNA modification is a major feature of cancer

The ribosome is an RNA-protein complex 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) gene are known drivers of oncogenesis, oncogenic rRNA variants have remained elusive. We discovered a cancer-specific single nucleotide variation at 18S.1248U in the 18S rRNA of up to 45.9% colorectal carcinoma (CRC) patients and across >22 cancer types. This is the site of a unique hyper-modified base, 1-methyl-3-α-amino-α-carboxyl-propyl pseudouridine (macpΨ), a modification that is >1 billion years conserved at the ribosome9s peptidyl decoding-site. A sub-set of CRC tumors we term 9hypo-macpΨ9, show sub-stoichiometric macpΨ-modification unlike normal control tissues. Our macpΨ knockout model and hypo-macpΨ patient tumors share a translational signature, characterized by highly abundant ribosomal proteins. Thus, macpΨ-deficient rRNA forms an uncharacterized class of 9onco-ribosome9 which may serve as an innovative chemotherapeutic target for treating cancer patients.