Over the course of a given day there are numerous forms of DNA damage that occur in cells. There are an estimated 103-105 damaging events/mammalian cell/day which reveals the dynamic state of DNA. As such, cells have developed a multitude of repair mechanisms to maintain DNA integrity.
Nucleotide excision repair was discovered roughly 55 years ago when studies showed that bacteria such as Escherichia coli after UV exposure could remove small fragments of DNA containing UV-induced damage. Even though studies on repair done in E. coli were instrumental in elucidating the mechanism and overall steps of NER, there is little homology between the two NER in prokaryotes and NER in eukaryotes, despite being a conserved repair mechanism. There are many eukaryotic NER proteins that do not correspond to a functional counterpart in prokaryotic repair and the mechanism of mammalian NER is far more complex than that of E.coli.
It was James Cleaver who recognized the connection between a deficiency in DNA repair and UV-sensitivity that ultimately leads to tumourigenesis. James Cleaver used xeroderma pigmentosum cell lines to show that UV-sensitivity is related to deficiency in NER in these patients. These results supported the notion that DNA repair played a pivotal role in the maintenance of genomic stability and preventing neoplastic transformation. The significance of NER is demonstrated by the existence of patients with autosomal recessive syndromes characterized by different deficiencies in NER, which include xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystropy (TTD). These syndromes are the result of a deficient protein involved in NER and therefore the outcome is a variety of serious clinical consequences including photosensitivity, neurodevelopmental abnormalities, ocular anomalies, decreased fertility and skin cancer in XP patients.
NER is divided into two pathways: global genome repair (GGR) and transcription-coupled repair (TCR). GGR eliminates lesions from the entire genome including from the non-coding region of the genome, the non-transcribed strand of active genes and from silent genes. On the other hand, TCR is responsible for repairing damage with higher priority from the transcribed strand of active genes. The only difference between the two NER pathways is the way the lesion is recognized. The stalled RNA polymerase II acts as a signal in TCR for recognizing the presence of a damaged site, while GGR uses a complex composed of three subunits, XPC, HR23B and centrin 2, which identifies the helical distortion and recruits the repair machinery.
Early reports showed that RNA synthesis is temporarily blocked after UVirradiation and that the recovery of RNA synthesis occurs faster in normal cells compared to that in CS and some XP cells. The slower recovery of RNA synthesis in CS cells was found to result from a deficiency in TCR of DNA lesions from the transcribed strand of active genes, rendering the cells sensitive to UV radiation. Increased efficiency of repair of the transcribed strand of active genes when compared to a sequence in a noncoding region downstream was first shown in Chinese hamster ovary cells. Subsequently, a preferential repair of the transcribed strand of active genes was also shown in human cells, in E. coli and in Saccharomyces cerevisiae.