Researchers at China Medical University discovered that reactive oxygen species (ROS) activate the DNA damage response (DDR) kinase CHK2, which then boosts Nrf2 antioxidant activity through two distinct mechanisms. CHK2 phosphorylates the autophagy adaptor p62 at serine-349, enabling it to outcompete Nrf2 for Keap1 binding and preventing Nrf2 degradation. CHK2 also directly phosphorylates Nrf2 at serines 566 and 577, amplifying its transcriptional output. In mice lacking CHK2, Nrf2 target gene expression is blunted and kidney damage from ischemia-reperfusion injury is significantly worse. This ATM-CHK2-Nrf2 axis represents a previously unrecognized molecular bridge between DNA damage sensing and cellular antioxidant defense.
