The versatile interactions of p53 with DNA: when flexibility serves specificity

The tumor suppressor p53 exerts versatile interactions withDNA. Of importance is the binding of wild-type p53 to p53-responsive elements in promoters of p53 target genes. Thisinteraction is complex and determined by DNA sequence andstructure, and involves the p53 core DNA binding and theC-terminal domain. In addition, wild-type p53 binds linearDNA with high affinity in a sequence-independent manner,andnon-BDNAinaDNAstrictlystructure-selectivemodethatis not dependent on the presence of a p53-responsiveelement. Mutant p53 has lost sequence-specific DNA bindingand high-affinity binding to linear DNA, but has retained theability to interact with DNA in a structure-selective manner.We discuss the interactions of p53 with DNA, which arecharacterized by a high flexibility, both on the side of p53 andDNA, thereby providing p53 with the specificity required for itsfunctions.The major molecular property of p53 is that of a DNAbinding protein. Consequently, its interaction with DNA iscentral to various p53-mediated activities. Best known andanalyzed is the sequence-specific DNA binding of p53 (p53-SSDB), followed by transcriptional activation of genesinvolved in regulation of the cell cycle, DNA repair orapoptosis,uponactivationofthep53pathwaybyendogenousor exogenous stress factors.