Transcriptional control of human p53-regulated genes

Abstract

The p53 pathway responds to various cellular stress signals by triggering the p53 protein, which mediates the transcriptional activation or repression of a host of target genes. We present and analyse a database of 160 experimentally validated p53-binding sites that regulate 122 genes in the human genome and 1 human-born virus. Profile hidden Markov models are presented to better capture the statistical characteristics of p53-binding sites compared with position-specific score matrices (weight matrices). Only ∼50% of the experimentally validated p53-binding sites are in the 5′ promoter-enhancer region of a gene. The remainder are found in exonic and intronic regions. Low-affinity p53-binding sites that poorly match the p53-binding site consensus exist only in a tight 'band' around the transcription start site (TSS) of a gene. A dynamic-acceptance threshold, which depends on the putative site distance from the TSS, can be used to reduce the false-positive rate during p53-site searches. p53-activator sites have a strikingly different distribution of spacer lengths compared with repressor sites. Most importantly, repressor sites do not show a great preference for 0-base-pair spacers. p53-repressor sites that regulate non-apoptosis genes have no preference for 0-base-pair spacers, whereas ∼50% of all known p53-binding sites have 0-base-pair spacers.