Functional Diversity in the Gene Network Controlled by the Master Regulator p53 in Humans

Abstract

Individual differences in susceptibility to exposure-induced diseases are likely due to variation in the DNA sequences of “environmental response” genes, many of which are arranged in complex regulatory networks. Among ~10 million inherited DNA variations, called single nucleotide polymorphisms (SNPs), perhaps only a few thousand, will actually influence human disease risk. We have combined bioinformatics and laboratory approaches to investigate genetic variation within the p53 stress response network. p53, a prominent tumor suppressor protein, is a master regulator that targets over a hundred genes for transcriptional up-regulation or repression through sequence-specific interactions with DNA response elements (REs). We identified many human genes in the network that contain SNPs in REs that can be transactivated by p53. The discovery of these individual differences has implications for variation in human responses to environmental stresses, risk of disease, and responsiveness to drug therapies. The findings also provide insight into the evolution of complex networks and the role of master regulatory genes, such as p53, in such networks.