XERODERMA-PIGMENTOSUM AND RELATED DISORDERS - EXAMINING THE LINKAGE BETWEEN DEFECTIVE-DNA REPAIR AND CANCER

Xeroderma pigmentosum, Cockayne syndrome, the xeroderma pigmentosum-Co ckayne syndrome complex, and trichothiodystrophy cells have defects in DNA repair and are associated with clinical and cellular hypersensiti vity to ultraviolet radiation (UV). Familial dysplastic nevus syndrome cells have UV hypermutability. Although xeroderma pigmentosum and dys plastic nevus syndrome have markedly increased cancer risk, Cockayne s yndrome and trichothiodystrophy do not. At the molecular level, these disorders are associated with several different genetic defects as evi denced by the existence of multiple overlapping complementation groups . Recent progress has been made in identifying the chromosomal locatio n and cloning the defective genes in these disorders. Using plasmid sh uttle vectors we have shown abnormal repair and mutagenesis of DNA dam aged by 254-nm (UVC) or 295-nm (UVB) radiation or the chemical carcino gen aflatoxin in cells from patients with xeroderma pigmentosum. Altho ugh xeroderma pigmentosum cells are defective in repair of all photopr oducts, Cockayne syndrome cells appear to be defective in repair of cy clobutane dimers and have normal repair of nondimer photoproducts. DNS cells have post UV plasmid hypermutability. These diseases may serve as models for examining molecular mechanisms of carcinogenesis in huma ns.