p53: master of life, death, and the epigenome

Abstract

Long understood as a bona fide tumor suppressor that safeguards the integrity of the genome via regulating numerous cellular outcomes, p53 may also exert its decisive and versatile functions by controlling DNA methylation. In this issue of Genes & Development, Tovy and colleagues (pp. 959-972) report that, in naïve mouse embryonic stem cells (ESCs), p53 controls DNA methylation homeostasis by regulating the expression of key counteracting components of the DNA methylation machinery. Their findings indicate that p53 may exert its "guardian of genome" duties at least in part via safeguarding the epigenome of ESCs.

Keywords: DNA methylation; p53; stem cells.

Figure 1.

p53 keeps DNA methylation in balance in naïve ESCs. The relative degree of DNA methylation in nuclei (shown schematically as an inner circle inside the bigger oval representing the cell) is kept under control by p53 that down-regulates Dnmt3a and Dnmt3b DNMTs responsible for de novo DNA methylation and up-regulates Tet1 and Tet2 components of demethylation machinery. This balance is perturbed by loss of functional p53 in ESCs with the subsequent stochastic increase in DNA methylation and clonal heterogeneity in both naïve ESCs and the differentiated progenitors.