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.
Single-nucleotide-resolution sequencing of human N 6 -methyldeoxyadenosine reveals strand-asymmetric clusters associated with SSBP1 on the mitochondrial genome
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.
Recombination is required for efficient HIV-1 replication and the maintenance of viral genome integrity
A long-standing question is why retroviruses package 2 copies of RNA genomes when each infection event generates only 1 provirus. Recombination increases genetic diversity and generates HIV-1 variants that are resistant to antivirals or can escape immune responses. It also plays an important role in shaping the HIV epidemic as evidenced by multiple circulating recombinant forms. Although the role of recombination in generating genetic diversity has been clear, it was unknown whether this process is required for efficient HIV-1 replication. This study demonstrates that when recombination is inhibited in a part of the HIV-1 genome, viral titers decreased, and proviruses had deletions in regions where recombination was blocked. These results illustrate that recombination is a mechanism required to maintain HIV-1 genome integrity and provide insights into the benefit of packaging 2 seemingly redundant RNA genomes: it allows recombination to take place to salvage genetic information.