Chromatin and DNA damage response complexes (DDR complexes)

Chromatin and DNA damage response (DDR) complexes are sophisticated multi-protein assemblies that detect, signal, and repair DNA lesions within the structural context of chromatin [1: Jackson & Bartek, 2009, Nature]. These complexes, including the MRN complex, BRCA1-A complex, and various ATP-dependent chromatin remodelers like SWI/SNF, coordinate the cellular response to genotoxic stress to maintain genomic integrity [2: Sulli et al., 2012, Trends in Genetics]. In many cancers, components of these complexes are mutated or dysregulated, leading to genomic instability that facilitates tumor evolution while simultaneously creating specific therapeutic vulnerabilities [3: Lord & Ashworth, 2012, Nature]. Modern oncology leverages these vulnerabilities through "synthetic lethality," where inhibiting a compensatory DDR pathway (e.g., using PARP inhibitors) leads to selective cell death in tumors with existing repair defects like BRCA1/2 mutations [4: O'Connor, 2015, Molecular Cell]. Current clinical research is expanding beyond PARP to target other DDR nodes such as ATR, ATM, and DNA-PK, aiming to overcome resistance and enhance the efficacy of conventional DNA-damaging therapies [5: Pearl et al., 2015, Nature Reviews Cancer].

Other names

DNA damage response machineryChromatin-remodeling DDR complexesDNA repair complexesDDR network

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