nucleotide excision repair

Some DNA damage is too big and too distorting for the single-letter handyman to handle: bulky chemical adducts, the UV-made thymine dimers that kink the helix, and other lesions that warp the double helix's shape. Nucleotide excision repair is the pathway built for these bulky, helix-distorting injuries. Where base excision repair erases one letter, nucleotide excision repair cuts out a whole short phrase.

Its logic is to recognise the distortion rather than the specific chemistry of the damage, which lets one pathway handle a wide variety of bulky lesions. Proteins detect the kink in the helix; a pair of cuts is then made in the damaged strand, one on each side of the lesion, releasing a short single-stranded segment — in humans roughly two to three dozen nucleotides long — that carries the damage away with it. A repair polymerase then fills the resulting gap by copying the intact opposite strand, and ligase seals the final nick. The bulky lesion has been excised along with a small surrounding patch, and replaced with a clean copy.

Nucleotide excision repair is what protects us from sunlight: it is the main route by which human cells clear UV-induced thymine dimers. Its importance is laid bare by xeroderma pigmentosum, a disease caused by inherited defects in this pathway, in which patients suffer extreme sun sensitivity, severe skin damage, and a thousand-fold increased risk of skin cancer because the dimers sunlight makes are never cleared. Bacteria run a parallel version using the UvrABC proteins, showing how ancient and essential this repair logic is.