Genome-wide translational responses to stress: a focus on ribosome stalling

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。蛋白质的组成被储存（“编码”）在信使RNA中。从信使RNA到蛋白质的转换遵循一种称为遗传密码的模式。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。核糖体由两部分（亚基）组成。这两个亚基彼此分离，并结合到信使RNA上翻译它（即读取它）。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。信使RNA的翻译过程可分为起始、延伸和终止三个阶段。起始包括两个亚基结合到信使RNA上并开始翻译（读取它）。之后，两个亚基在读取信使RNA（延伸）时沿着信使RNA移动，直到到达末端（终止）。翻译通常在起始位点受到调控（即，通过决定哪些mrna被翻译）。然而，翻译也可以在延伸水平上进行调节，通常是通过“冻结”信使RNA上的核糖体并停止读取过程。这种现象被称为核糖体“失速”。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。在我的实验室里，我们研究了一种简单的酵母——由一个单细胞构成——它可以对许多不同类型的压力做出反应。利用这种酵母菌，我们发现当细胞受到压力时，它们会停止信使RNA特定位置的延伸过程。有趣的是，核糖体停滞的位置取决于它们所能获得的营养物质的种类。我们想了解这种停滞是否发生在其他情况下（我们已经尝试了3次），核糖体如何“知道”何时何地停止，以及这种行为如何对细胞有益。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。

Genome-wide translational responses to stress: a focus on ribosome stallingOur 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. The composition of a protein is stored ('encoded') in the messenger RNA. The translation from the messenger RNA to the protein follows a pattern called the genetic code.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. Ribosomes are made of two parts (subunits). The two subunits are separate from each other, and get together onto a messenger RNA to translate it (i.e., to read it). Studying translation is relevant for human cells, because the mechanisms that regulate translation often go awry during cancer and several inherited conditions.The process of translating a messenger RNA can be divided into three phases, called initiation, elongation and termination. Initiation involves the two subunits binding together to a messenger RNA and start translating (reading it). After that, the two subunits move along the messenger RNA as they read it (elongation) until they reach the end (termination). Translation is often regulated at the place of initiation (i.e., by deciding which mRNAs get translated). However, translation can also be regulated at the level of elongation, usually by 'freezing' the ribosomes on the messenger RNA and stopping the reading process. This phenomenon is called ribosome 'stalling'.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. In my laboratory, we study a simple yeast -made of a single cell- that can react to many different types of stress. Using this yeast, we have discovered that when cells get stressed, they stop the process of elongation at specific positions of the messenger RNA. Interestingly, the position where the ribosomes stall is different depending on the kind of nutrients available to them. We would like to understand if this kind of stalling happens in other situations (we have tried 3), how the ribosomes 'know' where and when to stop, and how this behaviour is beneficial for a cell. We expect this information will be useful to understand how human cells behave and, eventually, help us devise cures for disease.