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Human cDNA clones that modify radiomimetic sensitivity of ataxia-telangiectasia (group A) cells

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Somatic Cell and Molecular Genetics

Abstract

Genes responsible for genetic diseases with increased sensitivity to DNA-damaging agents can be identified using complementation cloning. This strategy is based on in vitro complementation of the cellular sensitivity by gene transfer. Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disorder involving cellular sensitivity to ionizing radiation and radiomimetic drugs. A-T is genetically heterogeneous, with four complementation groups. We attempted to identify cDNA clones that modify the radiomimetic sensitivity of A-T cells assigned to complementation group [A-T(A)]. The cells were transfected with human cDNA libraries cloned in episomal vectors, and various protocols of radiomimetic selection were applied. Thirteen cDNAs rescued from survivor cells were found to confer various degrees of radiomimetic resistance to A-T(A) cells upon repeated introduction, and one of them also partially influenced another feature of the A-T phenotype, radioresistant DNA synthesis. None of the clones mapped to the A-T locus on chromosome 11q22-23. Nine of the clones were derived from known genes, some of which are involved in cellular stress responses. We concluded that a number of different genes, not necessarily associated with A-T, can influence the response of A-T cells to radiomimetic drugs, and hence the complementation cloning approach may be less applicable to A-T than to other diseases involving abnormal processing of DNA damage.

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Authors and Affiliations

  1. Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, 69978, Ramat Aviv, Israel

    Yael Ziv, Anat Bar-Shira, Adam Sartiel & Yosef Shiloh

  2. Department of Radiation Medicine, Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, 3970 Reservoir Road NW, 20007-2197, Washington DC

    Timothy J. Jorgensen & Pamela S. Russell

  3. Department of Human Genetics, Roswell Park Cancer Institute, 14263, Buffalo, New York

    Thomas B. Shows & Roger L. Eddy

  4. Department of Genetics, Research Institute and Department of Molecular and Medical genetics, University of Toronto, M5G 1X8, Toronto, Ontario, Canada

    Manuel Buchwald

  5. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Boulevard, 77030, Houston, Texas

    Randy Legerski

  6. Department of Biological Sciences, Stanford University, 04305-5020, Stanford, Califormia

    Robert T. Schimke

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  1. Yael Ziv
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Ziv, Y., Bar-Shira, A., Jorgensen, T.J. et al. Human cDNA clones that modify radiomimetic sensitivity of ataxia-telangiectasia (group A) cells. Somat Cell Mol Genet 21, 99–111 (1995). https://doi.org/10.1007/BF02255785

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