A new insight into base excision repair (BER) in targeted cancer therapy
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A new insight into base excision repair (BER) in targeted cancer therapy Rakesh Kumar1,2,3 Received: 19 August 2020 / Revised: 5 September 2020 / Accepted: 15 September 2020 © Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare 2020
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, ROSassociated, 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. Keywords DNA damaging therapies · BER · UNG2 · Therapeutic resistance · ROS biology · Epigenetic combination therapy
Introduction All living beings have the instinct to resist their demise by triggering the activation of survival mechanisms to defend against any arising death signals and overtime, develop coping mechanisms to both tolerate and endure repeat survival threats. This underlining principle of living beings, i.e. an attempt to rapidly build up and engage survival mechanisms to counteract threat signals, is also true at the cellular, biochemical and molecular levels for both the healthy and cancer cells. The ratio of the cell death versus survival signals and their successful and timely execution also creates a threshold tipping point for an impending outcome, * Rakesh Kumar [email protected] 1
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala, India
2
Division of Hematology and Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark, USA
3
Department of Human and Molecular Genetics, Virginia Commonwealth University Medical Center, Richmond, USA
cell death versus cell survival. In this context, modulation of such a threshold in cancer cells in favor of cell death— largely by impairing the ability of cancer cells to repair damaged DNA for maintaining the genomic integrity of target cells—constitutes an underlying goal for developing effective anti-cancer therapies. Here I will attempt to highlight Bao’s article, “UNG2 deacetylation confers cancer cell resistance to hydro
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