BIOCHEMICAL MECHANISMS OF OXIDATIVE DNA DAMAGE AND ITS ROLE IN CANCER: CHEMICAL APPROACHES TO REPAIRING DNA DAMAGE

Abstract

Oxidative DNA damage has a major role in the initiation of carcinogenesis by inducing mutagenesis, genomic instability, and cellular dysfunction. Most of the time, reactive oxygen species (ROS), which are produced from various metabolic processes and from environmental influences, cause DNA lesions such as strand breaks, base modifications, and DNA-protein crosslinks. If not repaired, these oxidative lesions can then lead to permanent changes in the DNA introducing oncogenic pathways, as well as the silencing or impairment of tumor suppressive functions. DNA repair mechanisms such as base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR) are thus important for the maintenance of genomic integrity, with their compromised functions being noted to occur very commonly in cancer cells, further increasing mutation rates and resistance to therapy.

The goal of this study is to provide an overview of the biochemical mechanisms underlying oxidative DNA damage, while also evaluating chemical approaches to DNA repair enhancement. The efficacy of small-molecule inhibitors, synthetic base analogs, and antioxidants to modulate DNA repair processes was assessed using in vitro and in vivo models. Importantly, results show that targeting key enzymes of repair increases repair rates and enhance cellular survival under oxidative stress. Also, DNA repair inhibitors could sensitize cancer cells to chemotherapeutic agents by taking advantage of their repair-deficient states. Overall, our findings reaffirm the potential therapeutic applicability of the modulation of DNA repair pathways toward preventing cancer and treating it once established. Further refinement of chemical strategies that target cancer-specific repair weaknesses is vital to curtail potential side effects. This study proposes that integration of DNA repair modulation with precision oncology holds promise to benefit patient outcomes and pave the way for new onco-drugs.