Nature doi:10.1038/nature24482 (2017)

Human ribosomes are complexes of 80 ribosomal proteins and four ribosomal RNAs (rRNAs) that are post-transcriptionally modified, primarily by 2′-OH ribose methylation and the conversion of uridines into pseudouridines (ψ). The functional consequences of rRNA modifications include regulation of RNA folding and stability, modulation of the activity of ribosome-targeting antibiotics, and dysregulation of protein synthesis as occurs in cancer. To begin to assess the role of specific modifications on ribosome function, Natchiar et al. mapped rRNA modifications onto the human 80S ribosome structure using cryo-electron microscopy to address their 3D environment. The authors found 136 individual rRNA modifications, mostly clustered in the interior of the ribosome at functional centers such as the peptide exit tunnel. Fifty-one of these are base modifications other than 2′-O-methylations or ψ, including several unusual modifications at nucleotide oxygen positions. Fifty-two modifications were found at unique sites not predicted from biochemically established databases, which might possibly affect translation and may be unique to the cancer cells used for the structural analysis. The authors also solved the structures of human ribosomes with three different antibiotics, showing that these inhibitors are in direct contact with or in close proximity to rRNA modification sites. These findings suggest that rRNA modification affects protein synthesis, recognition of inhibitors and tRNAs, and may act as markers of dysregulated ribosomes.