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.
Phase separation (PS) drives subcellular compartmentalization that underlies the formation of non-membrane bound RNA-protein granules such as stress granules. Disturbance in stress granule dynamics is thought to drive pathological inclusions in several neurodegenerative diseases. Understanding the processes underlying PS of protein/RNA complexes and their progression to pathological aggregate will help understand disease progression. Here the authors measured the RNA induced PS of full length TIA-1 protein and the formation of amyloid-like fibres. They determined that while a single site oligonucleotide induced conformational change, tandem sites were required and sufficient to promote PS. The PS was finely tuned according to protein:RNA binding site stoichiometry rather than RNA length. Tandem TIA-1 binding sites within native target 3’UTR RNA promoted TIA-1 PS. The study provides insight into the way stress granule formation may be initiated and modulated by TIA-1/RNA interactions.
Power-law behavior of transcription factor dynamics at the single-molecule level implies a continuum affinity model
Transcription factors (TF) must engage with chromatin to regulate gene expression. Using single-molecule tracking, it is now possible to follow individual TF molecule tracks inside live cells. As the TF moves around the nucleus, it travels through a rugged energy landscape of binding affinities. Current interpretations of dwell times for transcription factors invoke a bi-exponential model, assuming that nonspecific interaction with chromatin corresponds to a fast component, while a slower component represents specific binding. In this study, investigators have shown that the bi-exponential model mis-represents the true interaction behavior of TFs. The authors first describe a rigorous treatment for photo-bleaching correction. Using this methodology, they find that transcription factor dwell time distributions are best described by a power-law model, and show how power-law distributions emerge as a result of a broad distribution of transcription factor-chromatin interaction affinities.
Viral infections often trigger the activation of a ribonuclease produced by the host, RNase L, that cleaves single-stranded regions of viral and host RNAs and promotes clearance of the virus. Widespread cleavage of messenger RNAs (mRNAs) leads to broad reduction in their abundance but it remains unknown how this reduced pool of mRNAs is translated. The authors performed ribosome-profilingto globally assess the distribution of ribosomes in RNase L activated cells. Surprisingly, RNase L activation led to an increase in the relative translation of regions of the mRNA that are not normally translated. Since this alternative translational program was dependent on the catalytic activity of RNase L, the authors proposed a model where cleavage of mRNA by RNase L leads to the translation of mRNA fragments. The resulting cryptic peptides that are synthesized could be presented on the cell surface by MHC-I molecules as a “non-self” signal to enhance viral clearance.