Visualization of chemical modifications in the human 80S ribosome structure

Abstract

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.

The mammalian mitochondrial epitranscriptome

“…This hypothesis has been proposed before on several occasions [45,80,102], and takes special relevance due to the functional and overall structural conservation of mitoribosomes versus ribosomes of other compartments and species, especially because the mitochondrial proteome is more restricted in number and diversity of its components. Furthermore, with the advent and optimisation of high throughput, transcriptome-wide techniques for the targeted detection of RNA modifications, as well as cryoEM [205], it will be now possible to dive to greater depths of biological detail and identify novel modified residues in mt-rRNA. For instance, in addition to the well-established aforementioned residues (Section 2), several novel m 1 A sites were recently reported for mt-rRNAs, which need to be given attention, not only in terms of verification, but also regarding the enzymes involved in their deposition and their functional relevance [201].…”

The nucleolar protein NOP2 is required for nucleolar maturation and ribosome biogenesis during preimplantation development in mammals

“…Indeed, a recent study confirmed the presence of m5C in human rRNAs, although its biological role remains unclear. 38 It has been demonstrated that NOP2 possesses m5C methyltransferase capability in yeast. 13 Because NOP2 depletion reduced rRNA abundance in preimplantation embryos, we sought to ask if the methyltransferase activity of NOP2 is responsible for its regulation on rRNA and essential for embryo development.…”

Enzymatischer oder In‐vivo‐Einbau von Propargylgruppen in Kombination mit Klick‐Chemie zur Anreicherung und Detektion von Methyltransferase‐Zielsequenzen in RNA

“…Angereicherte und abgereicherte Peaks wurden identifiziert und ihre Positionen mit bekannten Methylierungsstellen in humaner rRNAv erglichen (Abbildung 3B,T abelle S2, Abbildung S14). [20]…”