DNA damage response machinery (DDR)

The DNA damage response (DDR) machinery is a complex network of signaling pathways and enzymatic processes dedicated to detecting, signaling, and repairing various types of DNA lesions to maintain genomic integrity (Lord & Ashworth, 2012). It encompasses several distinct pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break repair via homologous recombination (HR) or non-homologous end joining (NHEJ) (O'Connor, 2015). In cancer, defects in these pathways often drive genomic instability but also create vulnerabilities that can be exploited through synthetic lethality, where inhibiting a compensatory repair pathway leads to selective cell death (Pearl et al., 2015). Therapeutic strategies targeting the DDR include PARP inhibitors for BRCA-mutant cancers and inhibitors of checkpoint kinases like ATR, ATM, and WEE1 to disrupt cell cycle control and sensitize tumors to DNA-damaging therapies (Lord & Ashworth, 2012). Clinical success in this area relies heavily on the use of biomarkers, such as BRCA1/2 mutations or HRD scores, to identify patients most likely to benefit (O'Connor, 2015). However, targeting these fundamental cellular processes carries risks of systemic toxicity, particularly myelosuppression, and the potential for developing drug resistance through secondary mutations (Pearl et al., 2015).

Other names

DNA repair pathwaysGenome maintenance machineryDNA damage response systemDNA repair network

Inhibition of specific DNA repair enzymes and checkpoint kinases to induce synthetic lethality or potentiate the effects of DNA-damaging agents.