RNA Binding and Metabolism: Elucidating the Role of Glycolytic Enzymes in Posttranscriptional Gene Regulation

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A cell is the smallest unit of an organism. All cells of every organism contain a copy of the same genetic information, which is organised into genes in the form of DNA. During the process of gene expression, DNA is copied to an intermediate molecule called RNA, which can then serve as a template for the synthesis of proteins. Proteins define the shape and function of each cell of the organism. Physically, RNAs are covered by proteins, so-called RNA-binding proteins. These proteins can remove or rearrange parts of the RNA, store, or deliver it to particular locations within the cell, and ultimately degrade it. They also control when and how messenger RNAs (mRNAs; refers to the class of RNAs that encode proteins) are translated into proteins. If an RNA-binding protein does not work properly, it can lead to malfunction of the cell and ultimately to disease. Due to their tremendous importance, we and other researchers have used a new experimental approach to catalogue all of the RNA-binding proteins that interact with mRNAs in cells. Besides detecting previously validated RNA-binding proteins, we found that many proteins with other well-established functions, such as enzymes, are also able to interact with RNA. Enzymes are proteins that perform essential chemical reactions; for instance, they provide and control the flow of energy required to keep cells alive. Whilst individual examples of enzymes binding to RNA have been characterised previously, the finding that most or even all enzymes of an important energy-generating pathway, termed glycolysis, interact with RNAs in yeast intrigued us. During glycolysis, glucose is transformed via a pathway involving several sequential steps, into another chemical. During this process, energy is generated. This important pathway is highly conserved in all organisms and is tightly controlled. In yeast, glycolysis is essential for the generation of ethanol from glucose, a feature of yeast that has been used for centuries for the production of wine, beer and other goods. In humans, the pathway is highly active in cancer cells and thus, provides a target for the development of new strategies for cancer treatment. Intrigued by our findings that all of the enzymes in this essential pathway bind to RNA, we wish to understand both the basis and the function of these interactions. Therefore, we propose to comprehensively identify the RNA targets for the enzymes of this pathway. We will then investigate where and how they bind to the RNA, and specifically abrogate mRNA-binding sites in cells, to see whether it affects the fate of particular mRNAs. Likewise, we will measure whether abolishing this binding has an effect on the activity of the protein encoded by the mRNAs and the associated pathway.With our research, we hope to discover previously unrecognised connections between RNA regulation and the chemical reactions that fuel cells. This knowledge is likely to have impact on diverse important aspects of our society, from food-production, to the development of new cancer treatments.