we report a negative correlation between oxidative DNA damage and activity of the antioxidant enzymes. Multiple antioxidant networks formed by interactions between the antioxidant enzymes and the proteins essential for maintenance of genomic integrity are indentified in the nucleus by multi-proteomic assays. The protein-protein interactions in these networks are significantly up-regulated under oxidative stress, as evidenced by quantitative proximity ligation assays in situ within single cells. The antioxidant enzymes in the networks catalyze the ROS dismutation cascade before ROS attacks the Fe-S cluster, thereby preventing DNA and the enzymes from oxidative damage and dysfunction. Our findings implicate that the antioxidant networks serve as a firewall role in maintenance of genomic integrity.