Nucleotide Excision Repair (Homo sapiens)

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NER was first described in the model organism E. coli in the early 1960s as a process whereby bulky base damage is enzymatically removed from DNA, facilitating the recovery of DNA synthesis and cell survival. Deficient NER processes have been identified from the cells of cancer-prone patients with different variants of xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne’s syndrome. These XP cells exhibited an ultraviolet radiation hypersensitivity leading to a hypermutability response to UV, offering a direct connection between deficient NER, increased mutations, and cancer. While the NER pathway in prokaryotes is unique, the pathway utilized in yeast and higher eukaryotes is highly conserved and includes a variety of proteins that interact to form complexes.
NER is involved in the repair of bulky adducts in DNA, such as UV-induced photo lesions [of both 6-4 photoproducts (6-4 pps) and cyclobutane pyrimidine dimer (CPDs)], intrastrand cross-links, large chemical adducts formed from exposure to aflatoxin, benzopyrene and other genotoxic agents. Specific proteins have been identified that participate in base damage recognition, cleavage of the damaged strand on both sides of the lesion, excision of the oligonucleotide bearing the lesion, and accessory proteins necessary for efficient function. Polymerization and ligation restore the strand to its original state. NER consists of two related pathways called global genomic repair (GG-NER) and transcription-coupled NER (TC-NER). The pathways differ in the way in which DNA damage is initially recognized, but the majority of the participating molecules are shared between these two branches of NER". GG-NER is considered to be transcription-independent, removing lesions from non-transcribed regions of genome in addition to non-transcribed strands of transcribed regions. The preferential repair of UV-induced damage in transcribed strands of active genes is known as Transcription-coupled NER (TC-NER).
Several of the proteins involved in NER are key components of the basal transcription complex TFIIH. NER proteins have also been shown to interact with the 19S regulatory subunit of the proteasome, suggesting a role in cellular regulation signal pathways. The establishment of mutant mouse models for NER genes and other DNA repair-related genes have been useful in demonstrating the associations between NER defects and cancer.