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.
Exonic splicing enhancer (ESE) sequences are bound by serine & arginine-rich (SR) proteins, which in turn enhance the recruitment of splicing factors. It was inferred from measurements of splicing that Drosophila doublesex ESEs are bound stably by SR proteins, and that the bound proteins interact directly but with low probability with their targets. However, it has not been possible with conventional methods to demonstrate whether mammalian ESEs behave likewise. Using single molecule multi-colour colocalization methods to study SRSF1-dependent ESEs, this study shows that the proportion of RNA molecules bound by SRSF1 increases with the number of ESE repeats, but only a single molecule of SRSF1 is bound, indicating that initial interactions between SRSF1 and an ESE are weak and transient, and limit the activity of a mammalian ESE. They tested whether the activation step involves the propagation of proteins along the RNA or direct interactions with 3′ splice site components by insertin ...
Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease
RNA molecules are modified to acquire chemical and functional diversity. tRNA modifications play a role in the fidelity of decoding by modulating codon–anticodon interactions on the ribosome. The optimal rate of translation, fine-tuned by tRNA modifications, is necessary for correct protein folding and maintenance of proteome integrity. In this study, the authors demonstrate the biosynthetic route by which the modified RNA base 5-taurinomethyluridine (τm5U) is generated at the anticodon wobble position in several mitochondrial tRNA species, and demonstrate how dietary deficiencies or metabolic disorders that cause inadequate levels of taurine lead to low frequency of τm5U modification and subsequent pathologies related to mitochondrial dysfunction. The authors show that in taurine-deficient conditions, glycine can replace taurine. This is the first instance of chemical switching of RNA modification under physiological conditions.
The CRISPR system is an adaptive prokaryotic viral defense system that involves a range of complex nucleoprotein machines and targeting RNA molecules that target and degrade invading viral nucleic acid. This field has progressed quickly and many mechanistic questions have been answered. One exception is the process of spacer capture and processing, coupled with integration into the host genome, which underlies the basis of adaptive immunity. This study presents a biochemical study of the spacer capture and integration process for the model subtype I-A system of S. solfataricus. Key observations include: specific integration in this system requires long leader sequences and ATP hydrolysis – breaking the prevailing paradigm; integration of spacers is accompanied by prespacer processing in a PAM-dependent manner; cas1-2 binds and protects prespacers, allowing processing by nucleases including Cas4, resulting in generation of substrates suitable for integration.