DNA Damage Response Pathway

The DNA damage response (DDR) pathway is a complex, evolutionarily conserved network of cellular processes that detect, signal, and repair various forms of DNA damage to maintain genome integrity. It is activated in response to both endogenous and exogenous sources of DNA damage. The DDR coordinates cell cycle checkpoints, DNA repair mechanisms, transcriptional programs, senescence induction, or apoptosis depending on the extent of the damage. Key components include sensors (e.g., MRN complex, RPA, Ku70/80), signal transducers (e.g., ATM, ATR, DNA-PKcs), and effectors (e.g., CHK1/CHK2 kinases; p53 tumor suppressor; BRCA1/BRCA2; RAD51; CDK inhibitors like p21). Major repair pathways within the DDR include homologous recombination (HR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), mismatch repair (MMR), and base excision repair (BER). Defects in DDR components can lead to cancer and other diseases. Many cancer therapies target the DDR to enhance tumor cell killing or protect normal cells.

Various, including inhibition of kinases (e.g., ATM, ATR, CHK1/2), interference with DNA repair mechanisms (e.g., PARP inhibition), or modulation of protein-protein interactions (e.g., MDM2 inhibition)