Abstract
The p53 protein ensures cellular fidelity by suppressing or killing cells under stresses that enhance the mutation rate. Evidence suggests that the p53 protein may also ensure the fidelity of the epigenome. In this study a group of drugs that alter the deoxycytosine methylation patterns in cellular DNA are shown to preferentially kill human and mouse cells that contain p53 mutations or deficiencies. These observations are extended to mice that contain p53 deficiencies or missense mutations in their genome, which are preferentially killed when compared to mice with a wild type p53 gene. This is also the case for human cancer cell xenografts containing p53 mutations, which preferentially are killed by these drugs when compared to similar tumors with wild type p53. The loss of p53 function enhances a synthetic lethality with drugs that block or alter the patterns of deoxycytidine methylation in the genome.
Highlights
The p53 protein is a transcription factor that responds to a wide variety of stresses
In addition to 5-aza-2-deoxycytidine, we found a number of DNA methylation inhibitors could induce greater levels of apoptosis in p53 deficient mouse embryo fibroblasts (MEFs) than in wild type cells both in cell culture and in vivo
Two previous publications reported that the DNA demethylation agent Decitabine unexpectedly induced more apoptosis in p53 null or mutated cells than in p53 wildtype cells [13, 19]
Summary
The p53 protein is a transcription factor that responds to a wide variety of stresses. These results were followed up by Leonova et al [13] who provided a mechanism for this observation She and her colleagues demonstrated that in the absence of wild type p53 epigenetic changes in the genome lead to the expression of repetitive DNA sequences and the resultant RNAs (some of which form extensive secondary structures) induced interferon production resulting in cell death (i.e. activation of the innate immune response). In addition to 5-aza-2-deoxycytidine, we found a number of DNA methylation inhibitors could induce greater levels of apoptosis in p53 deficient MEFs than in wild type cells both in cell culture and in vivo These results were extended to live mouse models and to human xenograft cancer models. These data contribute additional evidence that the p53 protein plays a critical role in epigenetic regulation that has important consequences for cancer treatments
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