Deciphering p53 signalling

The tumour suppressor protein p53 orchestrates the cellular response to damage. p53 can induce repair processes, arrest cell growth and, in extreme cases, initiate controlled cell death (apoptosis). Failure of p53 to enact appropriate responses to stress can result in accumulation of aberrant cells. Accordingly, mutations in p53 are frequently found in cancers, highlighting its importance in maintaining healthy cell populations.
p53 is tightly controlled by post-translational modifications (PTMs), but the molecular details of how such modifications contribute to p53 activity are poorly understood. This project builds on a unique combination of expertise to enable a detailed in vitro investigation into how p53 is controlled by PTMs. Specifically, we will deploy synthetic protein chemistry approaches developed in the Muller lab to access site-specifically modified p53. We will then measure how PTMs modulate the overall structure and dynamics of p53 as well as p53's interactions with protein and DNA partners using technologies developed by Fluidic Analytics (diffusive sizing) and the Politis lab (structural mass spectrometry). These emerging analytical technologies are particularly valuable in light of the fact that p53 contains many disordered regions and is therefore difficult to characterize using traditional structural biology methods. As such, this proposal is interdisciplinary in that it combines synthetic chemistry and novel biophysical technologies to address a biological question.
Acetylation of p53 in the C-terminal region is associated with an increase in p53's ability to specifically bind to DNA targets and induce the expression of nearby genes. The molecular details that control this switch in p53 activity are fiercely debated. This studentship therefore aims to directly measure how p53 is controlled by PTMs by biophysically characterising semi-synthetic, site-specifically acetylated full-length p53.