Genome-wide translational responses to stress: a focus on initiation

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Our bodies are made of very different types of cells: Skin cells are flat and protect our body, while brain cells have cables that pass messages around. Despite being so different, all our cells carry exactly the same information in their genes. What makes them special is what information they use, that is, which genes they switch on and off.Cells need to respond to changes in their environment (stress) to avoid damage or even death. Stress conditions include high or low temperatures, lack of nutrients or a poor supply of oxygen. Cells react to stress by varying the way in which they use the information from their genes.The information on how to make a cell is stored in the form of a DNA molecule. However, this information cannot be read directly: it first needs to be copied into another molecule called messenger RNA (mRNA), from which it can be 'translated' into a protein. Proteins are the components that directly build the cell and make it function, and it is also proteins that are responsible for protecting the cell from the damage caused by stress.Cells react to stress by switching on 'defence' genes and by switching off the genes that are not needed during the response to stress. The process of turning on and off genes often takes place at the level of the translation of messenger RNAs (that is, by selecting which messenger RNAs will be translated into proteins). Translation is performed by tiny machines within the cells called ribosomes. Studying translation is relevant for human cells, because the mechanisms that regulate translation often go awry during cancer and several inherited conditions.Our aim is to understand how cells change the information they use - especially through translation - to cope with situations of stress. Two questions are particularly important: where do ribosomes start reading the messenger RNA? How frequently do they start reading it? This information is crucial, because it determines how much of the protein is produced through translation of the messenger RNA - and therefore whether the gene will be switched on or not.A recently-developed experimental technique allows us to detect all ribosomes on messenger RNAs as they prepare for the process of translation, giving us information about how translation changes in different situations. We will apply this method to study how cells modify translation of messenger RNAs in response to several stress conditions, and to understand how these changes help cells survive.One way to study a complicated process of the human body is to use a model organism: this is a simpler creature, but similar enough to allow us to learn about ourselves. To study these questions we will employ a simple yeast -made of a single cell- that can react to many different types of stress. We will investigate how the yeast cells regulate translation in response to stress: which mechanisms they use, which genes are turned on an off, and what is the importance of these genes. We expect this information will be useful to understand how human cells behave and, eventually, help us devise cures for disease.