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.
By combining single-molecule tracking, single-cell protein quantitation, quantitative kinetic analysis, and genetic engineering, the authors have made novel discoveries on how the behavior of a metal-responsive transcription regulator in live bacterial cells challenges two long-standing mechanistic paradigms in regulator-DNA interactions.
The identity and methylation status of the first transcribed nucleotide in eukaryotic mRNA 5′ cap modulates protein expression in living cells
Using in vitro generated capped mRNA, the influence of the first transcribed nucleotide and its methylation status on translation was systematically studied. Translation rates were found to depend strongly on the identity of the nucleotide and its methylation, mRNA purity and the immune state of the cell. These findings are of broad interest both in terms of describing potential strategies to improve expression of exogenous proteins (for applications such as gene therapies) while also providing considerable new insights in the mechanisms of regulation of mRNA translation.
Structural basis of non-canonical transcriptional regulation by the σA-bound iron-sulfur protein WhiB1 in M. tuberculosis
This study reports the structure of the WhiB1 bacterial transcription factor bound to the C-terminal domain of the primary sigma factor σA (σA CTD) from M. tuberculosis. This protein, like others in the Wbl protein family, contains a [4Fe-4S] cluster and is widely distributed in actinobacteria. WhiB proteins play versatile roles in diverse biological processes. WhiB1 is of particular interest because it is essential for cell growth, and it is suggested to have a role in the initiation of dormancy in response to nitric oxide (NO). NO is a potent antimicrobial chemical produced by the host to combat tuberculosis infection. Consequently, the transcription factors in the defense system of M. tuberculosis that swiftly sense and respond to NO are critical for the survival and pathogenesis of the bacterium. The reactivity of the [4Fe-4S] cluster in WhiB1 is highly selective for NO over O2, making it a specific NO sensor in aerobic bacteria.