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.
Telomeres are special structures at the ends of linear chromosomes. Maintenance of functional telomeres is essential for genome stability, and dysregulation of telomere synthesis is one of the hallmarks of cancer. Human telomeres consist of several kilobases of repeated DNA sequences, terminating in a 3’ single-strand Grich DNA overhang. The overhang is synthesized by telomerase, which is often regarded as the essential regulator of overhang length. Here, the laboratory of Carolyn M. Price laboratory reports that filling-in of the recessed, C-rich strand is as important as the for maintaining human telomere length as telomerase itself. They mutated CTC1, a subunit of a multiprotein complex that aids in synthesis of the C-rich strand. Loss of CTC1 leads to gradual telomere shortening, akin to what is observed in cells that lack telomerase. In the absence of CTC1, telomerase continues to extend the G-rich DNA overhang, but the elongated overhang cannot be converted to double-stranded D ...
Toxin-antitoxin systems become activated in bacteria under stress conditions and enable bacterial cells to survive episodes of stress including antibiotic challenges. This phenomenon is called persistence and contributes to the difficulties in treating relapsing, chronic and biofilm producing bacterial infections. This paper shows how the ratio of CcdB toxin to CcdA antitoxin determines transcriptional regulation of the ccdAB module. Depending on the exact ratio, CcdA can combine with CcdB and multiple low-affinity binding sites on operator DNA to form helical assemblies of alternating chains of CcdA and CcdB dimers that cover the operator and repress transcription of the ccdAB operon; alternatively, the two proteins can form DNA-free heterohexamers that relieve repression. The study uncovers an unusual mechanism of transcriptional regulation and helps to better understand the features of toxin-antitoxin systems.
Structured and disordered regions cooperatively mediate DNA-binding autoinhibition of ETS factors ETV1, ETV4 and ETV5
The ETS gene family comprises a large number of mammalian transcription factors. Many individual factors within that family are associated with human cancer development and progression through a variety of mechanisms. ETS transcription factors are subject to a diverse range of regulatory strategies, including autoinhibition of their DNA binding properties. Autoinhibition occurs through several divergent mechanisms for different family members, and can be controlled via post-translational modifications and protein-protein interactions. The authors posit that such regulation provides a source of specificity within such families of related DNA binding proteins. The studies in this paper utilize a combination of biochemical and structural approaches (including both X-ray crystallography and NMR spectroscopy) to identify novel autoinhibitory elements in ETV1, ETV4, and ETV5, both structured and instrinsically disordered, and to describe the mechanisms by which they affect DNA binding.