DNA repair pathways (NER, BER, HR, NHEJ)

DNA repair pathways are conserved mechanisms by which cells detect and correct genomic lesions — up to 100,000 per cell per day from endogenous sources (reactive oxygen species, replication errors, spontaneous hydrolysis). Four major pathways handle distinct damage types: nucleotide excision repair (NER) removes bulky adducts including UV-induced pyrimidine dimers; base excision repair (BER) corrects small oxidative lesions such as 8-oxoguanine; homologous recombination (HR) restores double-strand breaks with high fidelity via the sister chromatid in S/G2 phase; non-homologous end joining (NHEJ) ligates broken ends rapidly but less accurately, dominating DSB repair in non-dividing cells. Repair capacity declines with age — NER efficiency drops measurably in fibroblasts from older donors — and genomic instability is a recognized hallmark of aging (Schumacher et al., Nature 2021). Progeroid syndromes offer causal evidence: NER defects cause xeroderma pigmentosum (1,000-fold elevated cancer risk) and Cockayne syndrome; DSB-repair defects underlie Bloom and Werner syndromes. Oldest-old genomics (Kim et al. 2018) shows enrichment for variants in ERCC2, RAD52, and XRCC5. Repair enhancement as an aging therapy is unresolved; SIRT6 stimulates HR and NHEJ as an active preclinical target.