Probing life-and-death switches using "designer" p53

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Proteins are molecular machines that control most biological processes. Among them, a protein called p53 acts as a safeguard against cancer in that it instructs cancers cells to self-destruct before they can multiply. Accordingly, malfunction of p53 is a prerequisite for most human cancers. It is therefore important to understand the molecular mechanism by which p53 operates, alone and in conjunction with other protein partners. At the molecular level, p53 receives a multitude of stress signals from cells that are deposited onto p53 in the form of covalent biochemical signals, so-called post-translational modifications. These signals form a type of code which p53 then integrates into a defined cellular response ranging from "business as usual" and targeted repair processes all the way to the initiation of cell death protocols. However, how exactly p53 and its protein partners decode post-translational modifications remains enigmatic. This proposal aims to unravel how p53 makes such life-and-death decisions by determining how specific post-translational modifications change the functional interactions between p53 and its protein partners. We are able to achieve this goal because we have developed chemical tools that allows us to synthesise "designer p53" carrying defined modifications. Upon synthesising new versions of "designer p53", we aim to reconstitute biochemical signalling processes in the test tube, allowing us to measure the effect of post-translational modifications under controlled circumstances. Specifically, we aim to address how p53 modifications act as molecular docking platforms to connect with known and new protein partners and convert these interactions into further biochemical signals. In this way, we will illuminate how p53 acts as a molecular signal integration device which sets the foundation for new quantitative insights into its action as a tumour suppressor.