An aberration in gamma-ray-enhanced reactivation of irradiated adenovirus in ataxia telangiectasia fibroblasts.
Ataxia telangiectasia (AT) is a rare human genetic disorder, whose numerous clinical hallmarks include a predisposition to lymphoreticular cancers and a hypersensitivity to conventional radiotherapy. Furthermore, AT cells in vitro exhibit a hypersensitivity to ionising radiation that appears to be correlated with an increased frequency of chromosomal aberrations, a resistance of de novo DNA synthesis to inhibition by radiation-induced DNA damage, a reduced mitotic delay and possible defects in DNA repair. In this study, a sensitive viral assay has been used to investigate the capacity of gamma-irradiated AT cells to support the replication of undamaged virus, as well as the extent to which the survival of radiation-damaged virus was affected by gamma-irradiation of these host cells prior to infection. The expression of such enhanced reactivation (ER) of both u.v.-irradiated (u.v. dose = 1.2 X 10(3) J/m2) and gamma-irradiated (dose = 2 Mrad) adenovirus type 2 (Ad2) was examined in a variety of normal and AT human fibroblast strains. Unirradiated and gamma-irradiated fibroblasts were infected with unirradiated or irradiated Ad2, either immediately or at different times after cell monolayer irradiation, and at 48 h after infection cultures were examined by indirect immunofluorescence to determine the number of cells in which Ad2 viral structural antigen (Vag) was expressed. For immediate infection of normal human fibroblasts, both a decrease in unirradiated virus expression and an increase in ER were observed with increasing gamma-ray dose to the cells. In contrast, AT fibroblasts were found to be deficient in gamma-ray ER of irradiated Ad2, and this defect appeared to be related to a marked relative radioresistance of unirradiated virus expression in AT compared to normal cells. The potential significance of these results is discussed in the context of mammalian ER, which is believed to be, at least in part, an expression of a mutagen-inducible (and possibly error-prone) DNA repair mechanism.
D000260:Adenoviruses, Human / Q000235:genetics; D000956:Antigens, Viral / Q000235:genetics; D001260:Ataxia Telangiectasia / Q000235:genetics*; D002478:Cells, Cultured / Q000528:radiation effects; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D006801:Humans; D014466:Ultraviolet Rays; D014779:Virus Replication / Q000528:radiation effects
D000956:Antigens, Viral; D004247:DNA