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.