DNA repair complex (DRC)

DNA repair complexes are multi-protein assemblies essential for maintaining genomic integrity by identifying and correcting lesions in the DNA structure (NIH, 2023). These complexes operate through several distinct pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break repair (Nature Reviews Molecular Cell Biology, 2019). In many cancers, specific DNA repair pathways are mutated or downregulated, leading to genomic instability and the accumulation of further mutations (PubMed, 2021). This vulnerability is exploited therapeutically through the concept of synthetic lethality, where inhibiting a compensatory repair pathway in a cell already deficient in another leads to selective cell death (StatPearls, 2023). Drugs such as PARP inhibitors have successfully utilized this approach in BRCA-mutant cancers by blocking the repair of single-strand breaks (Journal of Clinical Oncology, 2022). Emerging therapies also target other complex components like ATR, ATM, and DNA-PK to sensitize tumors to chemotherapy or radiation (Clinical Cancer Research, 2020). However, targeting these complexes can lead to systemic toxicities, such as myelosuppression, and the development of drug resistance through the restoration of repair capacity (FDA, 2023). Furthermore, the loss of DNA repair fidelity is a hallmark of aging and various neurodegenerative disorders, suggesting broader roles for these complexes beyond oncology (Cell, 2020).

Other names

DNA damage response machineryDNA repair machineryDNA repair pathwaysDDR complexes

Inhibition of specific enzymes within the DNA repair complex to prevent the repair of DNA lesions, leading to cell death via synthetic lethality or potentiation of exogenous DNA damage.