DNA Binding Cooperativity of p53 Modulates the Decision between Cell-Cycle Arrest and Apoptosis

Summaryp53 limits the proliferation of precancerous cells by inducing cell-cycle arrest or apoptosis. How the decision between survival and death is made at the level of p53 binding to target promoters remains unclear. Using cancer cell lines, we show that the cooperative nature of DNA binding extends the binding spectrum of p53 to degenerate response elements in proapoptotic genes. Mutational inactivation of cooperativity therefore does not compromise the cell-cycle arrest response but strongly reduces binding of p53 to multiple proapoptotic gene promoters (BAX, PUMA, NOXA, CASP1). Vice versa, engineered mutants with increased cooperativity show enhanced binding to proapoptotic genes, which shifts the cellular response to cell death. Furthermore, the cooperativity of DNA binding determines the extent of apoptosis in response to DNA damage. Because mutations, which impair cooperativity, are genetically linked to cancer susceptibility in patients, DNA binding cooperativity contributes to p53's tumor suppressor activity.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (422 K)Download as PowerPoint slideHighlights► p53 DNA-binding domains interact to allow cooperative DNA binding ► DNA binding cooperativity enables p53 recruitment to proapoptotic target genes ► Cooperativity enhances p53-mediated apoptosis in response to DNA damage ► Cooperativity-reducing p53 mutations are genetically linked to cancer susceptibility