CELLULAR MECHANISMS OF DNA REPAIR IN RESPONSE TO GENOTOXIC STRESS

Abstract

Genotoxic stress, resulting from physical, chemical, or biological agents, poses a significant threat to genomic integrity by inducing various forms of DNA damage, including single- and double-strand breaks, base modifications, and bulky lesions. To maintain cellular homeostasis and prevent mutagenesis, cells rely on sophisticated DNA repair mechanisms that identify, signal, and rectify these lesions with high specificity and fidelity.This study systematically investigates the four principal DNA repair pathways—base excision repair (BER), nucleotide excision repair (NER), double-strand break repair (DSBR), and mismatch repair (MMR)—highlighting their molecular components, mechanisms, and context-specific activation under genotoxic conditions. The research further explores the roles of key proteins such as PARP1, ATM, BRCA1/2, RAD51, and XPA in orchestrating pathway-specific responses.The findings reveal elevated BER and HR activity in metabolically active and proliferative tissues, respectively, while a marked decline in NER and MMR efficiency was observed in aging and cancerous cells. Additionally, the therapeutic efficacy of PARP inhibitors in homologous recombination-deficient tumors was confirmed, along with the successful application of CRISPR-Cas9 for correcting BRCA1/2 mutations in targeted models.These results underscore the central role of DNA repair in both disease progression and treatment. By demonstrating the pathway-specific vulnerabilities in cancer and the age-related decline in repair capacity, this study supports the advancement of targeted therapies, including gene editing and synthetic lethality approaches. Understanding the cellular mechanisms of DNA repair in response to genotoxic stress provides a foundation for the development of precision medicine strategies and opens new avenues for combating cancer, neurodegenerative disorders, and premature aging.