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

我们的身体是由非常不同类型的细胞组成的：皮肤细胞是扁平的，保护我们的身体，而脑细胞有传递信息的电缆。尽管各不相同，但我们所有的细胞都携带着完全相同的基因信息。它们的特别之处在于它们使用的信息，也就是说，它们打开和关闭的基因。细胞需要对环境（压力）的变化做出反应，以避免损伤甚至死亡。压力条件包括高温或低温、缺乏营养或氧气供应不足。细胞对压力的反应是改变它们利用基因信息的方式。关于如何制造细胞的信息以DNA分子的形式存储。然而，这些信息不能直接读取：它首先需要被复制到另一种称为信使RNA （mRNA）的分子中，然后再被“翻译”成蛋白质。蛋白质是直接构建细胞并使其发挥功能的成分，也是负责保护细胞免受压力造成的损害的蛋白质。细胞对压力的反应是开启“防御”基因，关闭在应对压力时不需要的基因。基因的开启和关闭过程通常发生在信使rna的翻译水平上（也就是说，通过选择哪些信使rna将被翻译成蛋白质）。翻译是由细胞内被称为核糖体的微小机器完成的。研究翻译与人类细胞相关，因为在癌症和一些遗传疾病中，调节翻译的机制经常出错。我们的目标是了解细胞如何改变它们使用的信息——尤其是通过翻译——来应对压力情况。有两个问题特别重要：核糖体从哪里开始读取信使RNA？他们多久读一次？这个信息是至关重要的，因为它决定了通过信使RNA的翻译产生多少蛋白质，从而决定了基因是否会被打开。最近开发的一项实验技术使我们能够检测信使rna上准备翻译过程的所有核糖体，从而为我们提供有关翻译在不同情况下如何变化的信息。我们将应用这种方法来研究细胞如何在几种应激条件下修改信使rna的翻译，并了解这些变化如何帮助细胞生存。研究人体复杂过程的一种方法是使用模式生物：这是一种更简单的生物，但足够相似，可以让我们了解自己。为了研究这些问题，我们将使用一种简单的酵母——由一个单细胞制成——它可以对许多不同类型的压力做出反应。我们将研究酵母细胞如何调节翻译以应对压力：它们使用哪种机制，哪些基因被打开或关闭，以及这些基因的重要性。我们期望这些信息将有助于理解人类细胞的行为，并最终帮助我们设计出治疗疾病的方法。

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.