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.
A Polycomb repressive complex is required for RNAi-mediated heterochromatin formation and dynamic distribution of nuclear bodies
RNA interference and Polycomb repression are two deep-rooted and widespread mechanisms for transcription repression in eukaryotes. Here we characterize, in the protist Tetrahymena thermophila, the EZL1 complex, with components conserved in metazoan Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). The EZL1 complex is required for histone H3 K27 and K9 methylation, transposable element control, and programmed genome rearrangement. EMA1, a helicase required for RNA interference, interacts with the EZL1 complex and is implicated in its recruitment. Binding of H3K27 and H3K9 methylation by PDD1—another Polycomb group protein interacting with the EZL1 complex—reinforces chromatin association of the EZL1 complex. Our results support the coupling of RNA interference and Polycomb repression, which coordinately regulate transcription and genome (re)organization.
miRNAs are short pieces of RNA that modify the expression of most genes. It is a well-known phenomenon that the levels of many miRNAs are differentiated in cancer. In the study, in over 10,000 TCGA cancer samples, over 3,600 cancer somatic mutations were identified and characterized in 29 genes playing a role in miRNA biogenesis. Some of the genes were overmutated in specific cancers and/or had recurrent hotspot mutations. The authors identified a list of miRNAs (including well-known cancer-related miRNAs) whose level was affected by particular types of mutations in either SMAD4, SMAD2, or DICER1 and showed that hotspot mutations in DICER1 not only decrease the level of 5p-miRNAs but also increase the level of 3p-miRNAs. The study presents a comprehensive atlas of mutations in miRNA biogenesis genes that may help in understanding the role of the particular genes in cancer, and may also be a useful resource of information for studying the function of these genes.
Regulation of ex-translational activities is the primary function of the multi-tRNA synthetase complex
In mammalian cells, several aminoacyl tRNA synthetases (aaRS) form a multimeric complex, the MSC, and some version of this complex is conserved in eukaryotes and a subset of Archaea, suggesting a critical role. It has been assumed that multimerization facilitates efficient protein synthesis via proximity/mass-action effects, and collapse of the complex via deletion of its adaptors is lethal. However, it has remained unclear why some but not all aaRSs require this multimeric form. The authors use an elegant genetic approach to produce substantive evidence that ArgRS and GlRS have functions beyond their roles in protein synthesis. While the core idea is not new, the authors have engineered cells to lack the MSC-binding leucine zipper domain of ArgRS while retaining its tRNA catalytic activity and used them to provide compelling biochemical and cellular supporting evidence. An interesting finding is that expression of only the leucine zipper domain caused GlnRS to be retained in the MSC