DNA Damage Response in Cancer: Mechanisms, Therapeutic Strategies, and Clinical Implications

The DNA damage response (DDR) is a critical cellular network that safeguards genomic stability by detecting and repairing DNA lesions, thereby preventing the accumulation of deleterious mutations. In normal cells, the DDR functions as a key tumor-suppressive mechanism by either restoring DNA integrity or initiating apoptosis when damage is irreparable. In cancer, however, this system is frequently compromised due to mutations in essential tumor suppressor genes such as BRCA1/2 and TP53, resulting in increased genomic instability and accelerated tumor progression.This dual role underscores the “double-edged sword” nature of the DDR: while its proper function prevents tumorigenesis, its persistence or adaptation in cancer cells can confer resistance to DNA-damaging therapies such as chemotherapy, immunotherapy, or radiation therapy.The DDR relies on core components, including sensor and effector signaling proteins (ATM, ATR, and DNA-PK), which detect DNA damage and activate downstream repair pathways such as base excision repair, nucleotide excision repair, mismatch repair, single-strand break (SSB) repair, homologous recombination (HR), and non-homologous end joining (NHEJ). Importantly, defects in specific DDR pathways create therapeutic vulnerabilities through the concept of synthetic lethality, whereby cancer cells become dependent on compensatory repair mechanisms such as HR or PARP-mediated single-strand break repair (SSBR).Targeted approaches, such as PARP inhibitors, have successfully exploited this weakness, and emerging inhibitors of DDR-related proteins (ATM, ATR, CHK1, CHK2, and WEE1) hold promise for enhancing the efficacy of DNA-damaging treatments.This Research Topic aims to highlight recent advances in understanding the cellular and molecular mechanisms of the DDR in tumorigenesis, as well as their implications for cancer diagnosis, prognosis, and treatment. We welcome original research articles, reviews, and short communications addressing, but not limited to, the following topics:- Molecular regulation of DDR pathways in normal and malignant cells- Alterations and mutations in DDR genes and their oncogenic consequences- Mechanisms of resistance to DNA-damaging agents and DDR-targeted therapies- Development and optimization of small-molecule inhibitors or other therapeutic agents targeting DDR components- Identification and validation of DDR-associated biomarkers for cancer detection and personalized treatmentOur goal is to foster mechanistic insights that drive therapeutic innovation and ultimately improve clinical outcomes for cancer patients. Topic editors: Wei Du, Surya Amarachintha Source: https://www.frontiersin.org/research-topics/79617/dna-damage-response-in-cancer-mechanisms-therapeutic-strategies-and-clinical-implications