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.
Highlights
The ribosome is a massive ribonucleoprotein particle (RNP) responsible for the transformation of genetic information encoded as nucleic acids into functional proteins encoded as amino acids
We identify a surprising 18S ribosomal RNA (rRNA) single-nucleotide alteration at the decoding core of the ribosomal peptidyl (P) site, affecting up to 45.9% of CRC patients, making this the most frequent ribosomal variant associated with cancer to date and potentially revolutionizing future chemotherapeutic strategies against this disease
To test for allelic selection that is inconsistent with neutral drift, the patient-matched difference in expressed variant allele frequency (VAF) was measured for deviation from zero for each position of 18S and 28S (Figure 1A)
Summary
The ribosome is a massive ribonucleoprotein particle (RNP) responsible for the transformation of genetic information encoded as nucleic acids into functional proteins encoded as amino acids. Unlike most RNPs, it is ribosomal RNA (rRNA) and not ribosomal proteins (RPs) that form the most ancient and catalytic core of the complex (Cech, 2000). The human ribosome contains >80 RPs and 4 rRNAs, totaling $80% of cellular RNA. During the initial human genome sequencing project, ribosomal DNA (rDNA) loci were systematically excluded from the reference genome (Lander et al, 2001), given that a reference sequence of the rRNA gene, RNA45S, was available and the 80–800 rDNA copies were believed to be homogeneous (Elder and Turner, 1995). As technology and sequencing consortium projects revolutionized genomics and transcriptomics, our understanding of rDNA variation has lagged
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