Investigation of the selective reprogramming of translation during apoptosis

蛋白质合成是将细胞中遗传物质中的信息，即DNA，通过中间底物mRNA转化为蛋白质的过程。要合成蛋白质，信使核糖核酸必须与称为核糖体的大型复合体相互作用，核糖体由RNA和蛋白质组成。核糖体能够破译信使核糖核酸中的遗传信息，并进行蛋白质的合成。有两种不同的机制可以使mRNAs与核糖体相互作用。最常见的机制需要蛋白质复合体与mRNA的5‘端结合，然后这个复合体招募核糖体。然而，某些mRNA包含不编码蛋白质片段的5‘区(称为非翻译区；UTRs)，这些RNA序列包含形成复杂RNA结构所需的信息。这些RNA结构允许核糖体被募集到mRNA中，通常距离5‘端相当远，因此这种核糖体募集的方法被称为核糖体内部进入。有趣的是，使用内部核糖体进入的信息通常编码与细胞生长和细胞死亡过程有关的蛋白质。我们已经证明，在细胞死亡期间，有选择地使用内部核糖体进入，以允许合成这一过程进行所需的蛋白质。这项建议的总体目标是了解这一机制在细胞凋亡中是如何发挥作用的。

Protein synthesis is the process by which the information in the genetic material in the cell, DNA is converted via an intermediary substrate mRNA, into proteins. For proteins to be synthesised the mRNA must interact with a large complex called the ribosome which consists of RNAs and proteins. Ribosomes are able to decode the genetic information that is held in the mRNA and carry out the synthesis of the proteins. There are two distinct mechanisms by which mRNAs can interact with the ribosomes. The most common mechanism requires the binding of a protein complex to the 5' end of the mRNA and this complex then recruits the ribosome. However, certain mRNAs contain 5' regions that do not code for sections of proteins (termed untranslated regions; UTRs) and these sequences of RNA harbour the information that is required to form a complex RNA structure. These RNA structures allow the ribosome to be recruited to the mRNA generally a considerable distance from the 5' end and so this method of ribosome recruitment has been termed internal ribosome entry. Interestingly, messages that use internal ribosome entry generally encode proteins that are involved in the processes of cell growth and cell death. We have shown that during cell death there is selective use of internal ribosome entry to allow synthesis of the proteins that are required for this process to proceed. The overall aim of this proposal is to understand how this mechanism functions during apoptosis.