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

DNA repair pathways are the conserved systems your cells use to find and fix genetic damage. The load is huge. Internal sources alone cause up to 100,000 lesions per cell per day. (Those sources are reactive oxygen species, copying errors, and spontaneous breakdown.) Four major pathways handle different kinds of damage. Nucleotide excision repair (NER) removes bulky distortions, like UV-induced pyrimidine dimers. Base excision repair (BER) fixes small oxidative lesions, like 8-oxoguanine. Homologous recombination (HR) repairs double-strand breaks accurately. It does so using the sister chromatid, in the S/G2 phase. Non-homologous end joining (NHEJ) glues broken ends back fast, but less accurately. It dominates 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). Premature-aging (progeroid) syndromes give causal evidence. NER defects cause xeroderma pigmentosum, with a 1,000-fold higher cancer risk. They also cause Cockayne syndrome. Defects in double-strand-break repair underlie Bloom and Werner syndromes. Genomics of the oldest old (Kim et al. 2018) shows enrichment for variants in ERCC2, RAD52, and XRCC5. Boosting repair as an anti-aging therapy is still unresolved. But SIRT6, which stimulates HR and NHEJ, is an active preclinical target.

Last reviewed: June 22, 2026

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