Cancer therapeutics produce reactive oxygen species (ROS) that damage the cancer genome and lead to cell death. However, cancer cells can resist ROS-induced cytotoxicity and survive. We show that nuclear-localized uracil-DNA N-glycosylase isoform 2 (UNG2) has a critical role in preventing ROS-induced DNA damage and enabling cancer-cell resistance. Under physiological conditions, UNG2 is targeted for rapid degradation via an interaction with the E3 ligase UHRF1. In response to ROS, however, UNG2 protein in cancer cells exhibits a remarkably extended half-life. Upon ROS exposure, UNG2 is deacetylated at lysine 78 by histone deacetylases, which prevents the UNG2–UHRF1 interaction. Accumulated UNG2 protein can thus excise the base damaged by ROS and enable the cell to survive these otherwise toxic conditions. Consequently, combining HDAC inhibitors (to permit UNG2 degradation) with genotoxic agents (to produce cytotoxic cellular levels of ROS) leads to a robust synergistic killing effect in cancer cells in vitro. Altogether, these data support the application of a novel approach to cancer treatment based on promoting UNG2 degradation by altering its acetylation status using an HDAC inhibitor. Image 1 • UNG2 confers cell resistance to H 2 O 2 , which can be targeted for cancer treatment. • UNG2 is deacetylated and stabilized in response to H 2 O 2 treatment. • E3 ligase UHRF1 interacts with and ubiquitinates acetylated UNG2 for proteasomal degradation. • Acetylation at K78 of UNG2 promotes UNG2-UHRF1 interaction and UNG2 degradation. • HDACi promotes acetylated-UNG2 degradation and enhances cancer toxicity of ROS reagents. [ABSTRACT FROM AUTHOR]