Three rare autosomal recessive syndromes are associated with a nucleotide excision repair (NER) defect: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and the photosensitive form of trichothiodystrophy (TTD). A common denominator of all three conditions is an extreme sensitivity to sunlight. XP patients exhibit in addition to photosensitivity a greater than thousand-fold increased frequency of sunlight-induced skin cancers. Other features include progressive degenerative alterations of the skin and eyes and in some cases accelerated neurologic degeneration due to increased neuronal death. Patients with CS have a combination of sun sensitivity, short stature, severe neurologic abnormalities due to dysmyelination, cataracts, dental caries, a wizened appearance, and a characteristic bird-like facies. They do not display cancer predisposition. The hallmark of TTD is sulfur-deficient brittle hair and nails. Patients also have ichthyosis and many symptoms characteristic of CS. About half of TTD patients are hypersensitive to ultraviolet (UV) light, and they have a NER defect. As in CS, there are no indications for an increased risk of cancer. In addition to the preceding, rare patients showing combined XP-CS symptoms have been described.
The NER pathway removes a remarkably wide array of structurally unrelated DNA lesions. Among these are numerous helix-distorting chemical adducts induced by carcinogens such as benz[a]pyrene, as well as cyclobutane pyrimidine dimers (CPD) and [6-4]pyrimidine-pyrimidone photoproducts (6-4PP) produced in human skin by the shortwave UV component of the solar spectrum. This explains why patients with inherited deficiencies in the NER process display marked hypersensitivity to sun exposure. Defective repair also results in genetic instability leading to increased chromosome abnormalities and mutagenesis and in many cases predisposition to cancer. At least two NER subpathways exist: a rapid transcription-coupled repair (TCR) pathway responsible for the efficient elimination of lesions from the transcribed strand of active genes that permits rapid resumption of the vital process of transcription and for some lesions a less efficient global genome repair (GGR) subpathway that surveys the entire genome.
Complementation analysis by cell fusion has allowed a further genetic classification of XP, CS, and TTD patients. In XP, seven different complementation groups are distinguished, representing seven distinct defective genes involved in NER in XP: XP-A, -B, -C, -D, -E, -F, and -G. In addition, another class of XP patients (XP variant) appears to be deficient in a gene product that in normal cells permits semiconservative replication of previously damaged sites in the DNA template (postreplication repair). Similarly, complementation analysis has revealed two complementation groups in CS, CS-A and CS-B, and three in TTD, of which two overlap with XP groups: TTD-A, XP-B, and XP-D. Patients with combined XP-CS have been assigned to three XP complementation groups: XP-B, XP-D and XP-G.
The NER defect in the cells of most XP and TTD patients is located in the core of the NER mechanism and affects both transcription-coupled and global genome repair. In XP-C cells the defect is limited to the global genome repair system, whereas in CS only the transcription-coupled repair pathway is impaired....