Facilitated search for specific genomic targets by p53 C-terminal basic DNA binding domain

p53 is a unique DNA binding protein with two distinct DNA binding domains, the central domain for sequence-specific DNA binding and the C-terminal basic DNA binding domain (BD domain) for structure-specific DNA binding. In contrast to the apparent inhibitory effect of the BD domain on p53 binding to sequence-specific DNA in vitro, here we demonstrate that the BD domain enhances p53 binding to the endogenous p21(Waf1) promoter and mediates rapid transactivation of p21.(Waf1) This paradox is resolved by the observation that the BD domain is required for rapid binding to non-sequence-specific genomic DNA (NS-DNA) as evident from global chromatin immunoprecipitation analysis of p53 DNA binding in vivo. This finding provides the first in vivo evidence from a eukaryotic system to support binding to NS-DNA as an intermediate step in searching for specific sites as proposed by von Hippel and Berg. Furthermore, we speculate that binding to structure-specific DNA by the BD domain is a mechanism for p53 rapid binding to genomic DNA from its free state to facilitate the search for its target sites in the genome undergoing genotoxic stress.