Transcriptional regulation by p53 through intrinsic DNA/chromatin binding and site-directed cofactor recruitment

The tumor suppressor protein, p53, plays a critical role in mediating cellu lar response to stress signals by regulating genes involved in cell cycle a rrest and apoptosis. p53 is believed to be inactive for DNA binding unless its C terminus is modified or structurally altered. We show that unmodified p53 actively binds to two sites at -1.4 and -2.3 kb within the chromatin-a ssembled p21 promoter and requires the C terminus and the histone acetyltra nsferase, p300, for transcription. Acetylation of the C terminus by p300 is not necessary for binding or promoter activation. Instead, p300 acetylates p53-bound nucleosomes in the p21 promoter with spreading to the TATA box. Thus, p53 is an active DNA and chromatin binding protein that may selective ly regulate its target genes by recruitment of specific cofactors to struct urally distinct binding sites.