Delayed expression of enhanced reactivation and decreased mutagenesis of UV-irradiated adenovirus in UV-irradiated ataxia telangiectasia fibroblasts
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Fibroblasts from patients with ataxia telangiectasia (AT) are hypersensitive to the lethal effects but hyposensitive to the mutagenic effects of ionizing radiation, suggesting that AT cells may be defective in some process which modifies damage to DNA. In this study we have examined the UV-enhanced reactivation (UVER) and UV-enhanced mutagenesis (UVEM) of UV-irradiated adenovirus in AT fibroblasts. UVER was examined using both V antigen expression as well as progeny production from infected cell cultures. Viral mutagenesis was studied by examining the induction of phenotypically wild-type revertants among the progeny obtained from fibroblasts infected with a temperature-sensitive early mutant of adenovirus (Ad5ts36). UVER factors for Ad V antigen expression were significantly less than normal in the AT strains tested when infection occurred immediately after UV-irradiation of cells. However, UVER factors were greater than 1 and similar to those found for normal strains when cells were infected 24 h after UV-irradiation, indicating a delay in the expression of UVER for Ad V antigen in AT cells. UV-irradiation of both normal and AT cells 24 h prior to infection also resulted in a significant increase in progeny survival for UV-irradiated Ad. In normal cells, this progeny UVER was concomitant with a significant increase in the mutation frequency for UV-irradiated virus (increase in targeted mutagenesis) suggesting the existence of an inducible error-prone DNA repair mode in normal human cells. In contrast, pre-UV-irradiation of AT cells resulted in a significant decrease in the mutation frequency for UV-irradiated virus. These results suggest that AT cells lack an inducible error-prone DNA mode and that the delayed expression of UVER in AT cells results from a relatively error-free mechanism.
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