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

Abstract

Highlights d 45% of colon cancers sub-stochiometrically lose m 1 acp 3 J ribosomal RNA modification d 22+ distinct cancer types show hypo-modification of m 1 acp 3 J d The >1-billion-years-conserved m 1 acp 3 J is involved in ribosomal P site stability d Loss of m 1 acp 3 J modification drives heterogenous translation of RP mRNAs

Profiling of ribose methylations in ribosomal RNA from diffuse large B-cell lymphoma patients for evaluation of ribosomes as drug targets

“…Here, we found SSU-m 1 acp 3 Ψ1248, SSU-m 7 G1639 and SSU-m 6 2 A1851 to be hypomodified in both cell lines and primary DLBCL, in contrast to LSU-m 1 A1309 and LSU-m 3 U4500 that were unaltered ( Supplementary Figure S4 and Supplementary Table S3 ). SSU-m 1 acp 3 Ψ1248 was recently found to be hypomodified in many cancer types ( 26 ). Thus, hypomodification in rRNA appears as a widespread phenomenon in cancer.…”

Ribosome Biogenesis Alterations in Colorectal Cancer

“…Suppression of Tsr3 in HCT-166 cells reduced the level of m 1 acp 3 Ψ to the one found in CRC samples [155]. The reduced level of m 1 acp 3 Ψ is predicted to alter the structure of the P site and resulted in an enrichment in a proliferative and translational gene signature at transcriptional or translational levels, that could drive colorectal tumorigenesis [155]. All these data show that subtle rRNA modifications originally thought to be structural elements of the ribosome can generate specific ribosomes with preferential translation of mRNAs coding for proliferative factors.…”

“…The C/D-Box small nucleolar RNA 16 (SNORD16) guides fibrillarin (FBL) to methylate the 2 O-ribose on the 18S-Am484 site and constitutes a molecular marker of CRC and a driver of colorectal tumorigenesis [154]. The ribosome biogenesis protein TSR3 induces the 1-methyl-3α-amino-α-carboxyl-propyl pseudouridine (m 1 acp 3 Ψ) modification on uridine U1248 of the 18S rRNA and is overexpressed in CRC and associated with colorectal tumorigenesis [155].…”

“…Crucial evidence of the importance of rRNA modifications in CRC was recently unveiled by the discovery of the reduced frequency of a single nucleotide variation in the 18S rRNA, present in 46% of CRC samples of four independent large cohorts (~10,000 patients) compared to patient-matched normal epithelium (n = 708) [155]. The nucleotide alteration was found by screening changes in the average variant allele frequency on rRNAs and occurs on uridine U1248 of the 18S rRNA which can display a chemical modification, a 1-methyl-3α-amino-α-carboxyl-propyl pseudouridine (m 1 acp 3 Ψ), thus leading to a decrease in 18S-m 1 acp 3 ΨU1248 level in CRC patients [155]. The ribosome biogenesis protein Tsr3 is an enzyme involved in this nucleotide modification which occurs in the peptidyl transferase center [169].…”

“…The ribosome biogenesis protein Tsr3 is an enzyme involved in this nucleotide modification which occurs in the peptidyl transferase center [169]. Suppression of Tsr3 in HCT-166 cells reduced the level of m 1 acp 3 Ψ to the one found in CRC samples [155]. The reduced level of m 1 acp 3 Ψ is predicted to alter the structure of the P site and resulted in an enrichment in a proliferative and translational gene signature at transcriptional or translational levels, that could drive colorectal tumorigenesis [155].…”