THE SINGLE-STRANDED-DNA END BINDING-SITE OF P53 COINCIDES WITH THE C-TERMINAL REGULATORY REGION

p53 is a transcription factor that binds double-stranded (ds) DNA in a sequence-specific manner. In addition, p53 can bind the ends of singl e-stranded (ss) DNA. We previously demonstrated that ssDNA oligonucleo tides interact with the C-terminal domain of p53 and stimulate binding to internal segments of long ssDNA by the p53 core domain. Here we sh ow that the p53 C-terminal domain can recognize staggered ss ends of d sDNA. We have mapped the binding site for ssDNA ends to residues 361-3 82 in human p53 using a p53 deletion mutant (p53-Delta 30) lacking the 30 C-terminal amino acid residues and a series of 22mer peptides. The binding site for DNA ends coincides with a region previously implicat ed in regulation of sequence-specific DNA binding by the core domain. The interaction of the C-terminal regulatory domain with the ends of s sDNA or with the protruding ends of dsDNA stimulates both sequence-spe cific and nonspecific DNA binding via the core domain. Electron micros copy demonstrated the simultaneous binding of p53 to dsDNA and a ssDNA end. These results suggest a model in which interaction of the p53 C- terminal tail with DNA ends generated after DNA damage causes activati on of sequence-specific p53 DNA binding in vivo and may thus provide a molecular link between DNA damage and p53-mediated growth arrest and apoptosis.