Adenosine to inosine RNA editing (A-to-I editing) is among the most prevalent epitranscriptomic changes found in metazoa. It is commonly believed that inosine is interpreted as guanosine by cellular machineries, most importantly during translation. In this study, investigators systematically examined ribosomal decoding using an unbiased mass spectrometry approach. They demonstrated that, while inosine is indeed primarily interpreted as guanosine, it can also be decoded as adenosine, and rarely even as uracil. In addition, the authors show that inosine causes ribosome stalling, especially when multiple inosines are present in the codon. The study demonstrates previously unappreciated functions for inosines in mRNAs, expanding the coding potential of edited mRNAs and affecting translational efficiency.
NAR’s Breakthrough Articles present high-impact studies answering long-standing questions in the field of nucleic acids research and/or opening up new areas and mechanistic hypotheses for investigation. These articles are chosen by the Editors on the recommendation of Editorial Board Members and Referees. Articles are accompanied by a brief synopsis explaining the findings of the paper and where they fit in the broader context of nucleic acids research. They represent the very best papers published at NAR.
This article describes the development of an unbiased single-nucleotide-resolution sequencing method to map 6mA within the human genome, and its application in a human genome-wide analysis. The study demonstrates that 6mA is enriched in active retrotransposons and that 6mA clusters are observable throughout the human mitochondrial genome, and consequently identified a putative mitochondrial 6mA reader and eraser. This finding provides a link between human 6mA and mitochondrial oxidative phosphorylation (‘OxPhos’) regulation.
In yeast, H3K4 methylation is carried out by the Set1 complex (Set1C). H2B ubiquitylation directly stimulates nucleosomal H3K4 methylation by Set1C. A minimal set of protein subunits and interactions are required for this process that includes Set1, Spp1 and several conserved Set1C subunits. This study examines how Set1C subunits sense H2B ubiquitylation and how they activate the catalytic function of Set1C to methylate nucleosomal H3K4. The study provides evidence that all essential components required for H2B ubiquitylation-dependent H3K4 methylation are interconnected within the active site of Set1C and are subjected to conformational changes upon sensing H2B ubiquitylation. It indicates that physical interaction of the N-terminus of Set1 with Swd1 located within the catalytic core enables Set1C to methylate nucleosomal H3K4 in the absence of Spp1. The study explains why ‘full-length’ Set1-containing Set1C is able to methylate H3K4 in the absence of Spp1.
