Loss of m(1)acp(3)Ψ 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 (m(1)acp(3)Ψ), a modification that is >1 billion years conserved at the ribosome’s peptidyl decoding-site. A sub-set of CRC tumors we term ‘hypo-m(1)acp(3)Ψ’, show sub-stoichiometric m(1)acp(3)Ψ-modification unlike normal control tissues. Our m(1)acp(3)Ψ knockout model and hypo-m(1)acp(3)Ψ patient tumors share a translational signature, characterized by highly abundant ribosomal proteins. Thus, m(1)acp(3)Ψ-deficient rRNA forms an uncharacterized class of ‘onco-ribosome’ which may serve as an innovative chemotherapeutic target for treating cancer patients