DNA Damage Response network (DDR network) (DDR network)

The DNA Damage Response (DDR) network is a comprehensive signaling framework that maintains genomic integrity by identifying and repairing DNA damage (O'Connor, 2015, Molecular Cell). It functions through a hierarchy of sensor proteins that detect lesions, transducer kinases like ATM and ATR that amplify signals, and effector proteins that execute repair or cell cycle arrest (Lord & Ashworth, 2012, Nature). This network is vital for preventing the accumulation of mutations that lead to cancer and other genomic instability syndromes. In oncology, the DDR network is a major therapeutic target because many tumors possess inherent defects in specific repair pathways, such as BRCA1/2 mutations in breast and ovarian cancers (Pearl et al., 2015, Nature Reviews Cancer). Drugs targeting the DDR network, including PARP, ATR, and ATM inhibitors, aim to exploit these vulnerabilities through synthetic lethality or by sensitizing cells to chemotherapy and radiation (Pilié et al., 2019, Nature Reviews Clinical Oncology). For instance, PARP inhibitors prevent the repair of single-strand breaks, which then convert to double-strand breaks that cannot be repaired in HR-deficient cells, leading to selective tumor cell death. Beyond PARP, inhibitors of ATR and CHK1 are being developed to disrupt the replication stress response, particularly in tumors with high levels of oncogene-induced stress. The clinical application of DDR-targeted therapies relies heavily on biomarkers like HRD status to identify patients most likely to benefit from treatment.

Other names

DNA damage response and repairDDR pathwayDNA repair networkGenomic integrity network

Inhibition of DNA repair enzymes to induce synthetic lethality; inhibition of checkpoint kinases to prevent cell cycle arrest and promote mitotic catastrophe in damaged cells; potentiation of DNA-damaging chemotherapy and radiotherapy.