Summary
Sixty-eight human fibroblast cell strains were assayed for radioresistant DNA synthesis (RDS), which is defined here as the absence of a steep component of inhibition of DNA synthesis in a dose-response curve when rate of DNA synthesis is plotted against radation doses from 0 to 20 Gy or more. Twenty-seven strains from patients who were previously diagnosed to have ataxia-telangiectasia (AT) were positive for this feature. Among the cell strains that did not show RDS were two from AT obligate heterozygotes (i.e., the parents of AT patients), two from patients with Alzheimer disease, two from patients with Friedreich ataxia, one from a patient with Bloom syndrome, one from a patient with Down syndrome, and six from patients with various immunodeficiencies. Four strains demonstrated RDS that was less pronounced than in most AT cells: one was from a patient with Nijmegen breakage syndrome, one was from a patient without ataxia but with choreiform movement disorder, telangiectasia, and elevated concentrations of α-fetoprotein in the blood, and two were from AT patients. RDS therefore is not a necessary trait of human genetic diseases that involve radiosensitivity or immunodeficiency. Although recent reports suggest that some AT patients do not exhibit RDS, we found RDS in all the AT cell we tested.
Similar content being viewed by others
References
Arlett CF, Priestley A (1985) An assessment of the radiosensitivity of ataxia-telangiectasia heterozygotes. In: Gatti RA, Swift M (eds) Ataxia-telangiectasia: genetics, neuropathology, and immunology of a degenerative disease of childhood. Liss, New York, pp 101–109
Barenfeld LS, Pleskach NM, Bildin VN, Prokofjeva VV, Mikhelson VM (1986) Radioresistant DNA synthesis in cells of patients showing increased chromosomal sensitivity to ionizing radiation. Mutat Res 165:159–164
Cox R, Masson WK, Weichselbaum RR, Nove J, Little JB (1981) The repair of potentially lethal damage in X-irradiated cultures of normal and ataxia telangiectasia human fibroblasts. Int J Radiat Biol 39:357–365
Dahle D, Griffiths TD, Carpenter JG (1979) Subchromosomal DNA synthesis in X-irradiated V-79 cells. Radiat Res 78:542–549
Edwards MJ, Taylor AMR (1980) Unusual levels of (ADP-ribose)n and DNA synthesis in ataxia telangiectasia cells following γ-ray irradiation. Nature 287:745–747
Erickson LC, Ross WE, Kohn KW (1979) Isolation and purification of large quantities of DNA replication intermediates by pH step alkaline elution. Chromosoma 74:125–139
Fiorilli M, Antonelli A, Russo G, Crescenzi M, Carbonari M, Petrinelli P (1985) Variant of ataxia-telangiectasia with low-level radio-sensitivity. Hum Genet 70:274–277
Ganges MB, Tarone RE, Jiang H, Hauser C, Robbins JH (1988) Radiosensitive Down syndrome lymphoblastoid lines have normal ionizing radiation-induced inhibition of DNA synthesis. Mutat Res 194:251–256
Houldsworth J, Lavin MF (1980) Effect of ionizing radiation on DNA synthesis in ataxia telangiectasia cells. Nucleic Acids Res 8:3709–3720
Jaspers NGJ, Gatti RA, Baan C, Linssen CML, Bootsma D (1988a) Genetic complementation analysis of ataxia telangiectasia and the Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet Cell Genet (in press)
Jaspers NGJ, Taalman RDFM, Baan C (1988b) Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia. Am J Hum Genet 42:66–73
Lehmann AR, Arlett CF, Burke JF, Green MHL, James MR, Lowe JE (1986) A derivative of an ataxia-telangiectasia (A-T) cell line with normal radiosensitivity but A-T-like inhibition of DNA synthesis. Int J Radiat Biol 49:639–643
Little JB, Nagasawa H (1985) Effect of confluent holding on potentially lethal damage repair, cell cycle progression, and chromosomal aberrations in human normal and ataxia-telangiectasia fibroblasts. Radiat Res 101:81–93
Makino F, Okada S (1975) Effects of ionizing radiations on DNA replication in cultured mammalian cells. Radiat Res 62:37–51
Ockey CH (1983) Differences in replicon behavior between X-irradiation-sensitive L5178Y mouse lymphoma cells and A-T fibroblasts using DNA fiber autoradiography. Radiat Res 94:427–438
Painter RB (1981) Radioresistant DNA synthesis: an intrinsic feature of ataxia telangiectasia. Mutat Res 84:183–190
Painter RB (1983) Are lesions induced by ionizing radiation direct blocks to DNA chain elongation? Radiat Res 95:421–426
Painter RB (1986) Inhibition of mammalian cell DNA synthesis by ionizing radiation. Int J Radiat Biol 49:771–781
Painter RB, Young BR (1975) X-ray-induced inhibition of DNA synthesis in Chinese hamster ovary, human HeLa, and mouse L cells. Radiat Res 64:648–656
Painter RB, Young BR (1980) Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc Natl Acad Sci USA 77:7315–7317
Paterson MC, MacFarlane SJ, Gentner NE, Smith BP (1985) Cellular hypersensitivity to chronic γ-radiation in cultured fibroblasts from ataxia-telangiectasia heterozygotes. In: Gatti RA, Swift M (eds) Ataxia-telangiectasia: genetics, neuropathology, and immunology of a degenerative disease of childhood. Liss, New York, pp 73–87
Povirk LF, Painter RB (1976) The effect of 313 nanometer light on initiation of replicons in mammalian cell DNA containing bromodeoxyuridine. Biochim Biophys Acta 432:267–272
Smith PJ, Paterson MC (1983) Effect of aphidicolin on de novo DNA synthesis, DNA repair and cytotoxicity in γ-irradiated human fibroblasts. Implications for the enhanced radiosensitivity in ataxia telangiectasia. Biochim Biophys Acta 739:17–26
Taalman RDFM, Jaspers NGJ, Scheres JMJC, Wit J de, Hustinx TWJ (1983) Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage Syndrome. Mutat Res 112:23–32
Walters RA, Hildebrand CE (1975) Evidence that X-irradiation inhibits DNA replicon initiation in Chinese hamster cells. Biochem Biophys Res Commun 65:265–271
Watanabe I (1974) Radiation effects on DNA chain growth in mammalian cells. Radiat Res 58:541–556
Wit J de, Jaspers NGJ, Bootsma D (1981) The rate of DNA synthesis in normal human and ataxia telangiectasia cells after exposure to X-irradiation. Mutat Res 80:221–226
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Young, B.R., Painter, R.B. Radioresistant DNA synthesis and human genetic disease. Hum Genet 82, 113–117 (1989). https://doi.org/10.1007/BF00284040
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00284040