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.
Proteomic identification of histone post-translational modifications and proteins enriched at a DNA double-strand break
This article reports an unbiased proteomic analysis of the protein factors and post-translational modifications (PTMs) of histones associated with the incidence of double-strand breaks (DSBs) in yeast. The authors found many histone PTMs that had been previously implicated in the DNA damage response, as well as multiple new histone PTMs enriched on chromatin bearing a DSB from budding yeast. One of these, methylation of histone H3 on lysine 125, has not previously been reported. Among over 100 novel proteins enriched at a DSB were the phosphatase Sit4, the RNA pol II degradation factor Def1, the mRNA export protein Yra1 and the HECT E3 ligase Tom1. Each of these proteins was found to be required for resistance to radiomimetics. The study indicates that Yra1 and Def1 are required for DSB repair per se, while Sit4 is required for rapid inactivation of the DNA damage checkpoint after DSB repair.
Mariner transposition is a complex reaction that involves three DNA sites and six chemical reactions, which is carried out by a single transposase protein in a highly regulated and coordinated manner. Despite being the most widespread of all eukaryotic DNA transposons, key aspects of the mechanism have remained unclear, namely, the dynamics of the transpososome in which transposition takes place, and the number and role of individual subunits during the reaction. The studies in this manuscript demonstrate that the active site of a Mariner transposase sequentially cleaves two DNA strands of opposite polarity. In addition to providing a definitive answer to a long-standing question, their results identify a new mechanism that extends the catalytic repertoire of a vast and diverse family of nucleases based on the RNase H structural fold.
Deletion of subtelomeric homologous (SH) sequences from S. pombe had no effect on major cellular functions, but implicated subtelomeric sequences in a novel defense mechanism against telomere shortening. SH sequences prevented deleterious inter-chromosomal end fusion by facilitating intra-chromosomal circularization. The cells survive loss of telomeres and SH by inter- or intra-chromosomal end fusions, taking advantage of other highly similar DNA sequences around subtelomeres. Furthermore, subtelomeres play roles in blocking the spread of heterochromatin into neighboring regions, ensuring that the genes residing there are expressed. Protection of the subtelomeric borders is mediated by changes in chromatin modification that result exhibiting a nucleosome-free configuration that blocks spreading of silent heterochromatin into subtelomere-adjacent euchromatin regions. Thus, this work has uncovered the cryptic functions of subtelomeres in chromosome homeostasis and gene expression.