DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis in human embryo lung fibroblast cells

When cells encounter genotoxic stress, sensors for DNA lesions stabilize and activate p53; the signals involved, however, are largely unclear. Inorganic arsenite is a ubiquitous environmental contaminant associated with an increased risk of lung and skin damage and cancer. Although DNA double-strand breaks and apoptosis may relate to arsenite-induced damage and carcinogenesis, the mechanism of action remains obscure. Here, we find that, in human embryo lung fibroblast (HELF) cells, arsenite induces the activation of dependent protein kinase catalytic subunit (DNA-PKcs), which then phosphorylates and activates c-Jun N-terminal kinases 2 (JNK2), but not JNK1. As a positive regulator of p53, JNK2 binds to p53 and prevents p53 from murine double minute 2 (mdm2)-mediated, ubiquitin-proteasome-dependent degradation. Knockdown of DNA-PKcs/JNK2 signal pathway or p53 reduces apoptosis but elevates the DNA damage induced by a high level of arsenite. These results suggest that DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Exposure of human embryo lung fibroblast cells to a high level of arsenite induces DNA damage and apoptosis. ► P53 plays a role in arsenite-induced DNA damage and apoptosis. ► Arsenite improves p53 activation by DNA-PKcs/JNK2 signal pathway. ► JNK2 binds to p53 and prevents p53 from mdm2-mediated, ubiquitin-proteasome-dependent degradation. ► DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis.