DNA damage response (DDR) pathways (DDR)

The DNA damage response (DDR) pathways represent a sophisticated network of cellular mechanisms designed to identify and correct various forms of DNA damage, thereby preserving genomic stability (Jackson & Bartek, 2009, Nature 461:1071-1078). These pathways include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break repair mechanisms like homologous recombination (HR) and non-homologous end joining (NHEJ). In many cancers, specific DDR pathways are mutated or downregulated, leading to an increased reliance on alternative repair mechanisms (O'Connor, 2015, Molecular Cell 60:547-560). This dependency provides a therapeutic window for DDR inhibitors, which can induce synthetic lethality—a state where the loss of two compensatory pathways leads to cell death, while the loss of either alone is compatible with life (Lord & Ashworth, 2012, Nature 481:287-294). Clinically, drugs like PARP inhibitors have successfully exploited these vulnerabilities in patients with BRCA mutations, and ongoing research is expanding into inhibitors of ATR, ATM, and DNA-PK to enhance the efficacy of chemotherapy and radiotherapy.

Other names

DNA repair pathwaysGenome maintenance pathwaysDNA damage response and repairDDR pathways

Inhibition of specific DNA repair enzymes (e.g., PARP, ATR, ATM) to prevent the repair of DNA lesions, leading to accumulated genomic damage and cell death, often through synthetic lethality in cells with existing repair deficiencies.