DNA damage response (DDR) complexes (DDR)

DNA damage response (DDR) complexes at double-strand breaks (DSBs) are multi-protein assemblies that detect, signal, and repair the most cytotoxic form of DNA damage [1, 3]. Upon the occurrence of a DSB, the MRN complex (comprising MRE11, RAD50, and NBN) recognizes the break and recruits the apical kinase ATM (Ataxia-telangiectasia mutated), which phosphorylates numerous substrates to initiate repair and cell cycle arrest [2, 4]. These complexes facilitate two major repair pathways: non-homologous end joining (NHEJ), which is rapid but error-prone, and homologous recombination (HR), which is high-fidelity but restricted to the S and G2 phases [3, 5]. In oncology, these complexes are targeted to exploit "synthetic lethality," where cancer cells with pre-existing repair deficiencies (such as BRCA1/2 mutations) become hypersensitive to the inhibition of a complementary DDR pathway [1, 2]. Drugs targeting DDR components, including PARP, ATR, ATM, and DNA-PK inhibitors, are currently used or under investigation to enhance the efficacy of DNA-damaging therapies or as monotherapies in genetically defined patient populations [1, 4]. The therapeutic goal is often to prevent the repair of DNA lesions, leading to catastrophic genomic instability and selective cancer cell death [2, 3]. These complexes also play a role in preventing neurodegeneration and immune dysfunction by maintaining genomic integrity in non-dividing cells [4, 5].

Other names

DNA damage response (DDR) machineryDouble-strand break (DSB) repair complexesDNA repair signaling networkDDR system

Inhibition of DNA repair enzymes to induce synthetic lethality or sensitize cells to DNA-damaging agents