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© 1983 Oxford University Press

research-article

Abnormal response of ataxia-telangiectasia cells to agents that break the deoxyribose moiety of DNA via a targeted free radical mechanism

Yosef Shiloh 1 2 3, Eynat Tabor 1 and Yachiel Becker 1

1Department of Molecular Virology, Hebrew University-Hadassah Medical Center POB 1172, Jerusalem 91 010, Israel
2Department Human Genetics, Hebrew University-Hadassah Medical Center POB 1172, Jerusalem 91 010, Israel

3To whom reprint request should be sent at Division of Genetics, The Children's Hospital, Medical Center, 300 Longwood Avenue, Boston, MA 02115, USA.

A defect in DNA repair coupled to anomalous DNA synthesis after induction of certain radiogenic DNA damage is suspected to underlie the radiosensitivity of cells from patients with ataxia-telangiectasia (A-T). The response of cultured skin fibroblasts from A-T patients and A-T heterozygotes to six agents inducing various levels of DNA strand breakage by different mechanisms was studied to obtain further information on the nature of the ‘A-T critical DNA lesion’. The A-T cells showed varying degrees of hypersensitivity to the cytotoxic action of the quinone-containing anti-tumor antibiotics streptonigrin and adriamycin and to hydrogen peroxide. This hypersensitivity was accompanied by reduced inhibition of DNA synthesis compared to normal cells after treatment with these agents. A limited degree of cellular hypersensitivity that was not sufficient to allow for definition of a separate sensitivity range was shown by A-T heterozygous cells. On the other hand, the A-T cells showed a normal response to paraquat, saframycin A and ellipticine. Taken together with previous results showing hypersensitivity of A-T cells to ionizing radiation, bleomycin and neocarzinostatin, these data indicate that the critical DNA lesion in A-T cells is a strand break caused by deoxyribose destruction following the action of free radicals targeted into the DNA.


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