Cellular DNA and DNA Damage Response (DDR) pathways (DDR)

Cellular DNA and the associated DNA Damage Response (DDR) pathways represent a critical biological system responsible for detecting and repairing genomic lesions caused by endogenous and exogenous stressors (Lord & Ashworth, 2012, Nature Reviews Cancer). DNA itself acts as a therapeutic target for classical cytotoxic agents like cisplatin and temozolomide, which form covalent adducts or cross-links that stall replication forks (Pommier et al., 2016, Chemical Reviews). The DDR network comprises specialized proteins, including sensors like the MRN complex, and master regulators such as ATM, ATR, and DNA-PK, which orchestrate repair through pathways like homologous recombination or non-homologous end joining (Jackson & Bartek, 2009, Nature). In many cancers, specific DDR components are mutated, creating dependencies that can be exploited via synthetic lethality, exemplified by the use of PARP inhibitors in BRCA-deficient tumors (O'Connor, 2015, Molecular Cell). Beyond oncology, the DDR is vital in preventing neurodegeneration and premature aging, as accumulated DNA damage can lead to cellular senescence or apoptosis (Madabhushi et al., 2014, Neuron). Current drug development focuses on inhibiting specific DDR kinases to enhance the efficacy of DNA-damaging therapies or to selectively kill cancer cells with existing repair defects (Brown et al., 2017, Cancer Discovery). These pathways also play a role in the immune response, as cytosolic DNA fragments resulting from damage can activate the cGAS-STING pathway (Li & Chen, 2018, Nature Reviews Immunology). Therapeutic challenges include the development of resistance through secondary mutations and the potential for systemic toxicity due to the essential nature of DNA maintenance in healthy cells (Bouwman & Jonkers, 2012, Cancer Discovery).

Other names

DNA Damage ResponseGenome Integrity Maintenance SystemDNA Repair PathwaysDNA Damage Signaling and Repair

DNA alkylation, DNA interstrand cross-linking, PARP inhibition, ATR inhibition, ATM inhibition, DNA-PK inhibition, and Topoisomerase inhibition.