How mutations shape p53 interactions with the genome to promote tumorigenesis and drug resistance.

Abstract

The tumor suppressive transcription factor p53 regulates a wide array of cellular processes that confer upon cells an essential protection against cancer development. Wild-type p53 regulates gene expression by directly binding to DNA in a sequence-specific manner. p53 missense mutations are the most common mutations in malignant cells and can be regarded as synonymous with anticancer drug resistance and poor prognosis. The current review provides an overview of how the extraordinary variety of more than 2000 different mutant p53 proteins, known as the p53 mutome, affect the interaction of p53 with DNA. We discuss how the classification of p53 mutations to loss of function (LOF), gain of function (GOF), and dominant-negative (DN) inhibition of a remaining wild-type allele, hides a complex p53 mutation spectrum that depends on the distinctive nature of each mutant protein, requiring different therapeutic strategies for each mutant p53 protein. We propose to regard the different mutant p53 categories as continuous variables, that may not be independent of each other. In particular, we suggest here to consider GOF mutations as a special subset of LOF mutations, especially when mutant p53 binds to DNA through cooperation with other transcription factors, and we present a model for GOF mechanism that consolidates many observations on the GOF phenomenon. We review how novel mutant p53 targeting approaches aim to restore a wild-type-like DNA interaction and to overcome resistance to cancer therapy.