Abstract
Dysregulation of redox homeostasis and the resulting generation of excessive reactive oxygen species (ROS) and oxidative DNA damage play an obligatory role in the progression of human cancer as well as therapeutic sensitivity to a variety of genome-targeting cancer drugs. In a recent study, Bao et al. (Free Radic Biol Med, 2020), present a novel mechanism that governs the sensitivity of certain cancer cells to DNA damaging therapies. The authors have identified a novel, ROS-associated, lysine acetylation modification in Uracil-DNA N-glycosylase 2 (UNG2)—a key understudied component of the base excision repair pathway, which primes UNG2 for subsequent ubiquitination by UHRF1 ligase, leading to coupling the UNG2 degradation to cancer cell death in a ROS-sensitive manner. Translational innovation of these mechanistic findings resides by the ability of epigenetic therapeutic inhibitors to elevate the levels of UNG2-Lys78 acetylation, leading to sensitizing ROS-resistant cancer cells to DNA damaging therapeutic agents. I close this commentary by briefly summarizing some outstanding questions and postulations in the field in the context of the novel findings presented by Bao et al.
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