DNAskaderespons

DNAskaderespons, or DNA damage response, is the cellular network that detects DNA damage, transduces signals, and coordinates repair and cell fate decisions to maintain genome stability. It encompasses damage sensing, signaling, and effectors involved in repair, replication, transcription, and cell cycle control.

Key sensors recognize different lesions. Double-strand breaks recruit the MRN complex (MRE11-RAD50-NBS1) and activate the ATM kinase, while replication stress and single-stranded DNA activate ATR with ATRIP. DNA-PKcs participates in non-homologous end joining. These sensors initiate signaling cascades that amplify damage signals and recruit repair factors to the site of damage.

Repair pathways within the DDR include base excision repair and nucleotide excision repair for chemically damaged bases; mismatch repair for replication errors; and double-strand break repair through homologous recombination or non-homologous end joining. HR relies on BRCA1/2 and RAD51; NHEJ uses Ku70/80 and DNA-PKcs. Choice depends on cell cycle phase and damage context.

DDR signaling enforces cell cycle checkpoints. ATM and ATR activate CHK2 and CHK1, which stabilize p53 and induce p21, causing cell cycle arrest. If lesions are irreparable, cells may undergo apoptosis or senescence; if repaired, normal progression resumes.

Dysfunction of the DDR is linked to genomic instability and cancer. Therapeutically, DDR inhibitors exploit synthetic lethality, notably PARP inhibitors in BRCA-mutant cancers, underscoring the DDR's clinical relevance in oncology and aging research.