OVEREXPRESSION OF THIOREDOXIN IN FANCONI-ANEMIA FIBROBLASTS PREVENTS THE CYTOTOXIC AND DNA-DAMAGING EFFECT OF MITOMYCIN-C AND DIEPOXYBUTANE

Adult T cell leukemia derived factor (ADF)/thioredoxin (Trx) is known to be an important intracellular antioxidant involved in a number of r edox reactions such as ribonucleotide reductase (RNR) as well as of ty rosinase. Since RNR is a key enzyme of nucleotide metabolism and DNA s ynthesis, a reduced Trx level would result in reduced enzymatic activi ty and cause DIVA damage, Furthermore, Trx is considered to be an effe ctive regulator of redox sensitive gene expression. The role of Trx in nucleotide metabolism and gene expression may be an explanation for i ncreased chromosomal instability as well as hypersensitivity towards o xygen, ROI and ROI generating agents, The activity of tyrosinase, the key enzyme of melanin biosynthesis, is influenced by the thioredoxin l evel and by superoxide radicals, Low thioredoxin levels and high super oxide concentrations activate tyrosinase causing hyperpigmentation of the skin, In addition to tile observed high superoxide concentration i n Fanconi anemia (FA) patients, a low thioredoxin level might be respo nsible for the hyperpigmentation (cafe-au-lait spots) in this disease, We observed that overexpression of the thioredoxin cDNA in FA fibrobl asts completely abolished the DNA damaging effects of mitomycin C and diepoxybutane and inhibited the constitutive activity of the nuclear f actor kappa B (NF-kappa B) in SV40 transformed FA fibroblasts, However , spontaneous chromosomal breakage was not affected. (C) 1998 Federati on of European Biochemical Societies.