RECOVERY OF THE NORMAL P53 RESPONSE AFTER UV TREATMENT IN DNA REPAIR-DEFICIENT FIBROBLASTS BY RETROVIRAL-MEDIATED CORRECTION WITH THE XPD GENE

Among the major responses of human cells to DNA damage is accumulation of the p53 tumor suppressor protein, which plays a crucial role as a cell-cycle checkpoint. We have already shown that this response is dif ferent in cells from the UV-hypersensitive human syndromes xeroderma p igmentosum (XP) and trichothiodystrophy (TTD), which overlap with each other and arise from mutations in genes involved in nucleotide excisi on repair. In this paper we report that correction of the repair defec t by retroviral-mediated transduction of the wild-type XPD gene in XP- D and TTD/XP-D untransformed primary fibroblasts leads to a normal p53 response in these cells, Thus, the complemented cells, like normal hu man fibroblasts, require higher UV doses (10 J/m(2)) for p53 induction than the parental repair-deficient XP-D or TTD/XP-D cells (both mappi ng at the XPD locus), which accumulate p53 protein at very low UV dose s (2.5 and 5 J/m(2)), The p53 protein levels return to normal 24 h aft er irradiation when W-induced lesions have been efficiently repaired b y the restored NER activity. These data confirm our earlier results th at p53 accumulation following UV treatment is directly related to the presence of unrepaired cyclobutane dimers on the transcribed strand of active genes.