DNA damage response (DDR)

The DNA damage response (DDR) is a sophisticated network of cellular signaling pathways that detect, signal, and repair DNA lesions, particularly double-strand breaks (DSBs) induced by ionizing radiation [1, 11]. This system functions through a coordinated cascade involving sensor proteins like the MRN complex, transducer kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-related (ATR), and downstream effectors like p53 and checkpoint kinases (CHK1/2) [10, 12]. These components work together to arrest the cell cycle, allowing time for repair via mechanisms such as non-homologous end joining (NHEJ) or homologous recombination (HR), or to trigger apoptosis if the damage is irreparable [2, 11]. In the context of oncology, the DDR is a major therapeutic target because many cancer cells possess inherent defects in specific repair pathways, creating a dependency on alternative DDR components [3, 7]. Pharmacological inhibitors of DDR proteins, including PARP, ATR, and DNA-PK inhibitors, are employed to exploit these vulnerabilities through synthetic lethality or to sensitize tumors to radiotherapy and DNA-damaging chemotherapy [4, 6]. However, targeting these pathways also presents challenges, such as potential toxicity to normal tissues and the development of drug resistance [4, 11].

Other names

Radiation-induced DNA damage responseDNA repair pathwayDDR signalingCellular response to DNA damage

Inhibition of specific enzymes within the DDR pathway (such as PARP, ATR, ATM, or DNA-PK) to prevent DNA repair, leading to synthetic lethality in repair-deficient cells or sensitization to DNA-damaging agents like radiation.