ABSTRACT
The genome of all living organisms is under permanent attack from endogenous metabolic byproducts and environmental factors that alter the chemical structure of DNA and corrupt its nucleotide sequence. A network of DNA repair systems has evolved to cope with these genotoxic insults by eliminating DNA damage from the genome. Nucleotide excision repair (NER) is the only pathway in mammalian cells that removes bulky DNA adducts induced by ultraviolet (UV) light and electrophilic chemicals. It consists of a ubiquitous ‘‘cut and patch’’ mechanism that operates by excision of a short single-stranded DNA fragment, followed by restoration of the duplex DNA structure through repair synthesis. This particular DNA repair mode was first discovered in Escherichia coli as an enzymatic system that excises UV-radiation products from DNA (1,2). Subsequently, a functionally similar excision process was identified in humans (3,4). It was found that patients with the rare disease xeroderma pigmentosum (XP), characterized by extreme photosensitivity and a 2000-fold increased incidence of sunlight-induced skin cancer, are defective in NER of UV damage. Individuals who suffer from this autosomal recessive disorder are classified into seven repair-deficient complementation groups designated XPA through XPG. These patients also have an increased incidence of internal tumors and, in some cases, neurological abnormalities, probably reflecting the importance of NER in the repair of endogenous DNA damage (5). Cells derived from XP individuals show elevated mutation rates because of misincorporation of bases opposite to the unexcised lesions during replication of the damaged DNA template.
