Dynamic phosphorylation in the post-transcriptional regulation of the Trypanosoma brucei cell cycle

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How do cells make sure that they duplicate themselves correctly? When cells grow and divide, they must coordinate the duplication and division of their content between the two daughter cells in an ordered process known as the cell cycle. Understanding the many processes that regulate the cell cycle is important as many diseases such as cancer and diabetes involve a breakdown in this regulation. This project will study an important part of the cell cycle control mechanism using an organism called Trypanosoma brucei as a simplified system. Proteins are produced by transcribing DNA into messenger RNA, and then translating the messenger RNA into proteins. Regulation can occur at many different points during this process to control when and how much protein is produced within the cell cycle. Modification of proteins by adding or removing a phosphate group, a process called dynamic phosphorylation, is an important contol mechanism in cell cycle regulation. We are studying Trypanosoma brucei as unusually it does not regulate the transcription of DNA. Instead, all the regulation occurs after transcription, allowing us to focus on these events. The way that T. brucei uses dynamic phosphorylation to regulate the cell cycle is not understood, but is likely to be novel. To understand how Trypanosoma brucei is able to regulate its cell cycle, we will first measure how much of each protein is produced at different time points in the cell cycle, and whether they are phosphorylated. By breaking proteins down into smaller chains called peptides, we can measure many thousands of peptides and phosphorylation sites using sophisticated machine called mass spectrometers. These measurements can be used to determine how much of each protein and phosphorylation site is present at each time point. This will produce a description of the cell cycle that can be interpreted to make a model explaining how it is regulated. We will then conduct experiments to see if what the model predicts is correct. If our experiments show the model is not right, we can use this new information to improve the model until the predictions agree with our experiments. As Trypanosoma brucei is a parasite of cattle and a pathogen of humans, what we learn in this study will contribute to the development of new drugs against the parasite. Better understanding of the fundamental processes regulating the cell cycle will also have an impact on other important diseases such as cancer and diabetes.