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Article Type

Review

Abstract

Background: Not long ago DNA has become the subject of interest for the pharmaceutical companies, that because its proven by medical and scientifical fields, that it’s the fundamental sources of proteins, which is the basic element in the cell, therefore, the interaction between the Drug and the deoxyribonucleic acid (DNA) is very important to therapeutic regimens success but in other side it has a dangerous effect like toxicity, and long-term genomic instability. Objective: The aim of this review is to focus on the different studies which examines the effect of different drug like the chemotherapy, antivirals, antibiotics, and immune-suppressants on DNA, and focus on the damages that occur due to this interaction alter like that which studied the repair pathways, and shape clinical outcomes. Unlike of the previous reviews, this review is consider as a descriptive reviews, this work try to answer on the unsolved research questions, compares conflicting evidence, and focus on the unsolved gaps. Methods: A structured search was performed in different scientific platforms like PubMed, Scopus, and Web of Science, in period from the 2000 to 2025, to collect the all studies which studied this topic, analyzed them and detected the limitations and gapes, trying to find the best pathways and solutions, for whom concern. Results: Drugs may induce both, the direct lesions (crosslinks, intercalation, alkylation) and the indirect effects (oxidative stress, epigenetic remodeling). DNA-repair pathways—NER, HR, BER, and NHEJ—can either promote tumor clearance when overwhelmed or enable resistance when efficient. Clinically, these processes explain therapeutic success but also it have a secondary malignancies, toxicities on organs, fertility disorders, and aging. The detection tools include Comet and micronucleus assays to γ-H2AX, adductomics, and mutational-signature sequencing, yet require integration and standardization for clinical translation. Therapeutic innovations include DDR inhibitors (PARP, ATR, Polθ) and nanoparticle delivery systems, which is promise in more precision but it’s still face resistance and safety challenges. Conclusions: There is a significant research gaps remain, especially in pediatric cohorts, mitochondrial DNA damage, long-term mutational scarring, and biomarker validation. The future of genotoxic therapy depends on biomarker-driven personalization, orthogonal DNA-damage readouts, and rational therapeutic combinations that balance cure with safety.

Keywords

DNA damage; DNA repair pathways; Chemotherapy and genotoxicity; Epigenetic alterations; Drug resistance; Biomarker- driven

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