Translational responses to stress: a global view

我们的身体由非常不同类型的细胞组成：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。尽管差异如此之大，但我们所有的细胞在它们的基因中携带着完全相同的信息。细胞的特殊之处在于它们使用了哪些信息，即它们开启和关闭了哪些基因。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。应激条件包括温度高或低、缺乏营养物质或氧气供应不足。细胞对压力的反应是通过改变它们使用基因信息的方式。关于如何制造细胞的信息以DNA分子的形式存储。然而，这种信息不能直接读取：它首先需要被复制到另一种称为信使RNA(信使RNA)的分子中，它可以从信使RNA‘翻译’成一种蛋白质。蛋白质是直接构建细胞并使其发挥功能的组成部分，也是负责保护细胞免受压力破坏的蛋白质。细胞对压力的反应是通过打开“防御”基因，并关闭在对压力的反应中不需要的基因。打开和关闭基因的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)。研究翻译与人类细胞有关，因为在癌症和几种遗传性疾病期间，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--特别是通过翻译--来应对压力情况。最近开发的一项实验技术允许同时检测细胞中每个信使RNA的翻译，从而为细胞如何调节翻译提供了前所未有的见解。这种方法是以核糖体的名字命名的，核糖体是执行翻译的细胞机器。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。研究人体复杂过程的一种方法是使用模型有机体：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--由单个细胞组成--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：它们使用哪些机制，哪些基因处于开启和关闭状态，以及这些基因的重要性是什么。我们希望这些信息将有助于了解人类细胞的行为，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). 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. A recently-developed experimental technique allows the simultaneous detection of the translation of every messenger RNA in the cell, thus providing unprecedented insight into how cells regulate translation. The method is called 'ribosome-profiling' after the ribosome, which is the cellular machine that carries out translation. We will apply this approach to study how cells modify translation of messenger RNAs in response to several stress conditions.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.