How nucleotide excision repair protects against cancer

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Abstract
Living cells respond to DNA damage by a variety of mechanisms, including a series of biochemical pathways called DNA repair. These include three discrete pathways for the excision of damaged bases, called base excision repair, mismatch repair and nucleotide excision repair (NER). NER in human cells is a complex biochemical process during which a large multiprotein complex is assembled at several types of base damage. This multiprotein complex (NER machine) catalyses the excision of damaged bases as oligonucleotide fragments. The RNA polymerase II basal transcription factor, TFIIH, is an integral component of the NER multiprotein complex. NER operates somewhat differently on DNA that is transcriptionally active (transcription-coupled repair) and that which is transcriptionally silent (global genome repair). Defective NER in humans caused by genetically inherited mutations in NER genes results in the skin-cancer-prone disease xeroderma pigmentosum. Hereditary defects in transcription-coupled NER can result in a disease called Cockayne syndrome, which is characterized by severe developmental and neurological disorders. Mutational inactivation of certain NER genes can result in a combined syndrome of xeroderma pigmentosum and Cockayne syndrome, or in yet another disease called trichothiodystrophy, which is characterized by brittle hair and nails. Cockayne syndrome, combined xeroderma pigmentosum/Cockayne syndrome complex and trichothiodystrophy are not usually associated with increased cancer risk. Mouse mutant strains generated by targeted gene replacement have been constructed to model these human NER-defective syndromes.