Cap-proximal nucleotides via differential eIF4E binding and alternative promoter usage mediate translational response to energy stress

The production of new proteins is a complex process that occurs in two steps known as transcription and translation. During transcription, the cell copies a section of DNA to make molecules of messenger ribonucleic acid (or mRNA for short) in the nucleus of the cell. The mRNA then leaves the nucleus and enters another cell compartment called the cytoplasm, where it serves as a template to make proteins during translation. A mRNA molecule contains a sequence of building blocks known as nucleotides. There are four different types of nucleotides in mRNA and the order they appear in the sequence determines how the protein is built. Both transcription and translation consume a lot of energy so they are highly regulated and sensitive to environmental changes. However, since transcription and translation happen in different cell compartments, it is not known if and how they are coordinated under stress. Tamarkin-Ben-Harush et al. studied transcription and translation in mouse cells that were starved of glucose. The experiments show that the identity of the very first nucleotide in the mRNA – which is dictated during transcription – has a dramatic influence on the translation of the mRNA, especially when the cells are starved of glucose. This first nucleotide affects the ability of a protein called eIF4E, which recruits the machinery needed for translation, to bind to the mRNA. The experiments also show that there is a dramatic increase in the number of distinct mRNAs that are transcribed from the same section of DNA but translated in a different way during glucose starvation. The findings of Tamarkin-Ben-Harush et al. show that transcription and translation are highly coordinated when cells are starved of glucose, allowing the cells to cope with the stress. The next step is to further analyze the data to find out more about how transcription and translation are linked.