DNA damage response machinery (DDR) (DDR)

The DNA damage response (DDR) machinery is a complex network of proteins and signaling pathways dedicated to identifying and repairing DNA lesions, thereby preserving genomic stability (Jackson & Bartek, 2009). In the context of oncology, tumor cells frequently exhibit defects in specific DDR pathways, such as homologous recombination (HR) deficiency due to BRCA1/2 mutations, which forces them to rely on alternative repair mechanisms for survival (Lord & Ashworth, 2012). This dependency creates a therapeutic window for “synthetic lethality,” where pharmacological inhibition of a compensatory DDR component (e.g., PARP) leads to catastrophic DNA damage and selective apoptosis in cancer cells while sparing normal tissue (O'Connor, 2015). Modern drug development focuses on targeting key nodes within this machinery, including ATM, ATR, DNA-PK, and CHK1/2, to either act as monotherapies in biomarker-selected populations or to potentiate the effects of traditional chemotherapy and radiotherapy (Pilié et al., 2019).

Other names

DNA repair pathwayDNA damage response systemGenome maintenance machineryTumor cell DNA repair network

Inhibition of specific DNA repair enzymes (e.g., PARP, ATR, ATM, CHK1/2) to induce synthetic lethality in repair-deficient cells or to sensitize tumor cells to DNA-damaging agents.