HNE-induced DNA damage signaling is mediated by sensor protein ATR/Chk1. Upon DNA damage, ATR activates the phosphorylation of checkpoint kinase, Chk1, which phosphorylates/inactivates Cdc25C. Chk1-mediated inactivation of Cdc25C and p53-independent activation of p21 both partially play a major role in deactivation of CDK1 kinase activity, leading to G2/M phase arrest by HNE. Simultaneously, HNE-induced phosphorylation of H2A.X at Ser-139 initiates the signal for the recruitment of DNA repair machinery. GSTA4-4 overexpression prevents HNE-induced DNA damage and cell cycle signaling events.