Preserving DNA integrity against the daily barrage of damaging agents is a major function of the tumour suppression protein p53. The p53 response is dynamic and strictly regulated, to ensure that p53 acts upon demand at the required location. Once elicited, p53 acts either by halting cell replication to prompt cellular repair or by terminally shutting down the damaged cell. P53 is largely regulated through port-translational mechanisms. Dampening down p53 once it has acted is critical for normal cellular function. In cancer, p53 is frequently mutated, which may lead not only to a loss of its tumour suppressive capacities but diabolically, also to the acquisition of new tumour promoting properties. Mutation of p53 may also interfere with its normally strict regulation: allowing for the accumulation of aberrant p53 to high levels.
A major aim in the battle against cancer is to deactivate drivers of tumour establishment and progression, such as mutant p53. It is our intention to adopt a genome-wide RNAi and high-content analysis to identify molecules that are able to impact on mutant p53 levels. These define potential targets for the development of drugs/inhibitors that can specifically target mutant p53 in human cancer cells.