The Maintenance of Epigenetic States by p53: The Guardian of the Epigenome

Abstract

The functions of the p53 tumor suppressor gene and its protein are to ensure fidelity of cellular replicative processes so as to minimize mutational errors even in the presence of a wide variety of environmental stresses. Among the stresses p53 senses and responds to are DNA damage including telomere erosion, hypoxia, nutrient deprivation, errors in ribosomal biogenesis, abnormal chromosome segregation and even the mutational activation of several diverse oncogenes. Each of these stresses increases the rate of mutagenesis and the frequencies of cancers. When a cell senses a stress, it signals to the p53 protein using a wide variety of protein modifications (phosphorylation, acetylation, methylation), which help to increase the half-life of the p53 protein and activate it as a transcription factor. The p53 protein then rolls out a transcriptional program resulting in cell cycle arrest, senescence, or apoptosis, repairing or eliminating the cell depending upon the cell type, its state of transformation or other environmental factors. That this is an important process is demonstrated by the observations that the p53 gene is the most commonly mutated gene in human cancers and individuals who inherit mutations in this gene develop cancers at a young age [1].