DNAschaderespons

DNAschaderespons, or DNA damage response (DDR), is a network of cellular pathways that detect, signal, and repair DNA lesions to maintain genome stability. The DDR is activated by a range of DNA insults, including single-strand breaks, double-strand breaks, replication stress, and bulky adducts. Damage detection is mediated by sensor proteins that recognize DNA structures; double-strand breaks are sensed by the MRN complex, which activates ATM, while replication stress and single-stranded DNA recruit RPA and activate ATR. Activated kinases propagate signals through transducer and effector proteins, coordinating cell cycle checkpoints, transcriptional responses, and repair processes. The major outcomes are cell cycle arrest to allow repair (via p53/p21, CHK1/CHK2), stabilization of replication forks, and, if damage is irreparable, senescence or apoptosis.

Repair pathways include non-homologous end joining (NHEJ) and homologous recombination (HR) for double-strand breaks; base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR) for various lesions. Translesion synthesis provides damage tolerance during replication. DDR is interconnected with chromatin remodeling and transcriptional programs to facilitate access to damaged sites.

Defects in DDR components predispose to cancer and developmental disorders; examples include BRCA1/2, ATM, and p53 pathway mutations. Therapeutically, DDR defects can be targeted by PARP inhibitors or exploited to sensitize tumors to radiation or chemotherapy, reflecting the DDR's role in precision oncology.