Visualization of chemical modifications in the human 80S ribosome structure

Chemical modifications of human ribosomal RNA (rRNA) are introduced during biogenesis and have been implicated in the dysregulation of protein synthesis, as is found in cancer and other diseases. However, their role in this phenomenon is unknown. Here we visualize more than 130 individual rRNA modifications in the three-dimensional structure of the human ribosome, explaining their structural and functional roles. In addition to a small number of universally conserved sites, we identify many eukaryote- or human-specific modifications and unique sites that form an extended shell in comparison to bacterial ribosomes, and which stabilize the RNA. Several of the modifications are associated with the binding sites of three ribosome-targeting antibiotics, or are associated with degenerate states in cancer, such as keto alkylations on nucleotide bases reminiscent of specialized ribosomes. This high-resolution structure of the human 80S ribosome paves the way towards understanding the role of epigenetic rRNA modifications in human diseases and suggests new possibilities for designing selective inhibitors and therapeutic drugs. A high-resolution structure of the human ribosome determined by cryo-electron microscopy visualizes numerous RNA modifications that are concentrated at functional sites with an extended shell, and suggests the possibility of designing more specific ribosome-targeting drugs. Mapping modifications in the 80S The two subunits of the ribosome are each anchored by a large RNA molecule. After their transcription, many of the nucleotides in these ribosomal RNAs (rRNAs) are modified. The importance of these modifications is reflected in the fact that mutations in them are the basis of many diseases. Bruno Klaholz and colleagues have determined a structure of the human ribosome that has sufficient resolution to map more than 130 rRNA modifications, some of which were unknown. Comparison to sites of modification in the prokaryotic ribosome suggests how additional modifications enable stabilization of the larger eukaryotic complex. These data will expand our understanding of disease mechanisms and may suggest new therapeutic strategies.