Abstract
The biological importance of nucleotide excision repair (NER) in humans has been indicated by studies of autosomal recessive human genetic disorders: xeroderma pigmentosum (XP) and Cockayne syndrome (CS), in which NER activity is impaired. XP patients are hypersensitive to Ultraviolet (UV) in sunlight and show an increased incidence of UV-induced skin cancers. Although CS patients are sensitive to UV, they have no predisposition to sunlight-induced skin cancer, but instead show severe developmental and neurological abnormalities as well as premature aging. Seven NER-deficient complementation groups have been identified in XP (XP-A to XP-G), and two in CS (CS-A and CS-B). In addition, XP-B patients and certain patients with XPD or XPG gene show features of CS in addition to symptoms of XP (XP-B/CS, XP-D/CS and XP-G/CS). The clinical features of CS in XP-G/CS patients are difficult to explain on the basis of a defect in NER.
We found that XPG forms a stable complex with TFIIH, which is active in transcription and NER. Mutations in XPG found inXP-G/CS patient cells that prevent the association with TFIIH, also resulted in the dissociation of CAK and XPD from the core TFIIH. These results provide an insight into the role of XPG in the stabilization of TFIIH and the regulation of gene expression, and provide an explanation of some of the clinical features of XP-G/CS.
