SET-mediated epigenetic dysregulation of p53 impairs Trichloroethylene-induced DNA damage response

Abstract

Abstract Trichloroethylene (TCE) is a major ground water pollutant which causes severe hepatic toxicity. Previously, we have identified histone chaperon, SET as a key mediator of TCE-induced liver cell apoptosis. DNA damage with p53 suppression and reduced tri-methylation at histone H3K79 (H3K79me3) were also found under the treatment of TCE. However, epigenetic mechanisms in TCE-associated DNA damage response still remain largely unknown. In this study, we evaluated TCE-induced DNA damage of hepatic cells in the absence of SET, analyzed levels of H3K79me3 and p53 in hepatic cells and in mice livers with carcinogenesis. Results suggested that SET partially suppressed H3K79me3 and interfering with DNA response via mediating down-regulation of p53 under treatment of TCE. To further figure out the regulatory cascade, DoT1L (regulator of H3K79me3) and p53 were knocked down in L-02 cells respectively. Additionally, extent of DNA damage along with alterations of H3K79me3 and p53 were also evaluated. Results indicated that reduced H3K79me3 could lead to down-regulation of p53 which further exacerbated TCE-induced DNA injury. These findings demonstrated that SET-H3K79me3-p53 served as an epigenetic regulatory axis involved in TCE-induced DNA damage response.