Figure 3: DNA damage induced by oxidative and carbonyl stresses and p53-dependent DNA damage response (DDR). Reactive oxygen species (ROS) and α,β-unsaturated carbonyl compounds produced by lipid peroxidation, such as MDA and HNE, trigger DNA damage, such as double-strand DNA breaks. ATM/ATR senses the breaks and activates p53 by phosphorylating Ser15; ATM/ATR also phosphorylates Ser345 of Chk1/Chk2 and activates Chk1/Chk2, which further activates p53 by phosphorylating Ser20. In cells with mild DNA damage, p53 drives expression of and p53R2, leading to cell cycle arrest and DNA damage repair. In cells with severe DNA damage, p53 drives Fas-R, Bax, Puma, Noxa, Apaf-1, and Pidd expression, activating intrinsic and extrinsic apoptotic pathways.