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Different Removal of Ultraviolet Photoproducts in Genetically Related Xeroderma Pigmentosum and Trichothiodystrophy Diseases¹

Laboratory of Molecular Genetics, UPR 42 Institut Fédératif CNRS, IFCI, Institut de Recherches sur le Cancer, 7 Rue Guy Moquet, 94801 Villejuif, France [E. E., X. Q., O. C-L., A. S., M. M.]; URA 1464 CNRS, Hôpital Cardiologique du Haut-Leveque, Avenue de Magellan, 33604 Pessac, France [F. B.]; TNO Nutrition and Food Research Institute, Genetic Toxicology, 2280 HV Rijswijk, the Netherlands [L. R.]; Departments of Cell Biology and Genetics [A. P. M. E., J. H. J. H., D. B.] and Clinical Genetics [W. J. K.], Erasmus University, 3000 DR Rotterdam, the Netherlands; Division of Radiation Biology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920, Japan [O. N.]; Istituto di Genetica Biochimica ed Evoluzionistica, CNR, 27100 Pavia, Italy [M. S.]; and Laboratory of Radiobiology and Environmental Health, University of California, San Francisco, California 94143 [J. E. C.]

To understand the heterogeneity in genetic predisposition to skin cancer in different nucleotide excision repair-deficient human syndromes, we studied repair of cyclobutane pyrimidine dimers (CPDs) and of pyrimidine(6-4)pyrimidone (6-4PP) photoproducts in cells from trichothiodystrophy (TTD) patients. TTD is not associated with increased incidence of skin cancer, although 50% of the patients are photosensitive and carry a defect in the nucleotide excision repair pathway, similar to Xeroderma pigmentosum patients. However, in striking contrast to TTD, Xeroderma pigmentosum is highly prone to cancer. To address this apparent paradox, two types of studies were conducted: (a) reactivation of UV-irradiated plasmids harboring actively transcribed reporter genes, with or without photolyase treatment before transfection of SV40-transformed fibroblasts; and (b) the kinetics of removal of UV-induced CPDs and 6-4PPs in genomic DNA by immunoblot analysis using lesion-specific mAbs in SV40-transformed and untransformed fibroblasts representative of all genetic TTD complementation groups. Results showed that all cell lines from photosensitive TTD patients efficiently express Cat or luciferase genes in transfected plasmids carrying non-CPD lesions, including 6-4PP, and display wild-type or near-wild-type (50–70% in 3 cell lines) 6-4PP repair in the overall genome after immunoblot analysis. However, CPD lesions (the repair of which is defective in the overall genome) also block the expression of the reporter gene in transfected plasmids. Two cell lines from nonphotosensitive TTD patients showed wild-type levels of repair for both photoproducts in overall genome. A model on the lesion-specific repair in the context of the molecular defect in TTD is proposed. The implication of the defective CPD repair and efficient 6-4PP repair subpathways in cancer prevention in TTD patients is discussed.

¹ This work was supported by "Association Francaise pour la Recherche sur le Cancer" Contract 2083 (Villejuif, France); the Fondation de France (Paris, France); the Federation Nationale des Groupements des Enterprises Françaises dans la Lutte contre le Cancer (Marseille, France); the European Science Foundation (Strasbourg, France); Commission of European Communities Contract EV5V-CT91-0034 (Brussels, Belgium); the Office of Health and Environmental Research, United States Department of Energy Contract DE-ACO3-SF01012 and the Associazione Italiana per la Ricerca sul Cancro. E. E. is a fellow from the "Ligue Nationale Française contre le Cancer" (Paris, France). X. Q. is a fellow from the "Institut de Formation Supérieure Biomédicale" (Villejuif, France).

² To whom requests for reprints should be addressed.

Received 5/15/95. Accepted 8/ 2/95.

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