Rely on Each Other: DNA Binding Cooperativity Shapes p53 Functions in Tumor Suppression and Cancer Therapy

SIMPLE SUMMARY: p53 is a DNA-binding protein that activates hundreds of genes, which act concertedly to suppress the development, expansion, and spreading of cancer cells. The remarkable tumor suppressive activity relies on p53′s ability to bind DNA not as a single molecule, but in a cooperative manner as a complex of four tightly interacting proteins. We describe the structural features of p53 that enable DNA binding cooperativity and review the implications for p53 function. In approximately 50% of cancers, p53 is inactivated by mutations that either distort the 3D structure of the protein or destroy points of DNA contact. In this review, we emphasize that an estimated number of 34,000 cancer cases annually are caused by a third class of so-called “cooperativity” mutations, which selectively compromise the cooperative nature of DNA binding. We highlight the unique characteristics of tumors with p53 cooperativity mutations and discuss personalized treatment options for these cancer patients. ABSTRACT: p53 is a tumor suppressor that is mutated in half of all cancers. The high clinical relevance has made p53 a model transcription factor for delineating general mechanisms of transcriptional regulation. p53 forms tetramers that bind DNA in a highly cooperative manner. The DNA binding cooperativity of p53 has been studied by structural and molecular biologists as well as clinical oncologists. These experiments have revealed the structural basis for cooperative DNA binding and its impact on sequence specificity and target gene spectrum. Cooperativity was found to be critical for the control of p53-mediated cell fate decisions and tumor suppression. Importantly, an estimated number of 34,000 cancer patients per year world-wide have mutations of the amino acids mediating cooperativity, and knock-in mouse models have confirmed such mutations to be tumorigenic. While p53 cancer mutations are classically subdivided into “contact” and “structural” mutations, “cooperativity” mutations form a mechanistically distinct third class that affect the quaternary structure but leave DNA contacting residues and the three-dimensional folding of the DNA-binding domain intact. In this review we discuss the concept of DNA binding cooperativity and highlight the unique nature of cooperativity mutations and their clinical implications for cancer therapy.