Possible role of chromatin alteration in the radiosensitivity of ataxia-telangiectasia.
Cells derived from individuals with ataxia-telangiectasia (A-T) are known to exhibit increased sensitivity to ionizing radiation and certain radiomimetic chemical agents. Here we summarize our findings regarding the role of chromosome damage and repair in this radiosensitivity. Lymphoblastoid cells derived from A-T homozygotes were characterized for initial chromosome (premature chromosome condensation) and DNA (neutral filter elution) damage and repair kinetics in cells from G1 and G2 cell cycle phases. Despite initial levels of DNA damage being similar to normal controls, A-T cells exhibited nearly a two-fold higher initial amount of chromosome damage. Different A-T cell lines exhibited differing chromosome repair capacities compared with control lymphoblastoid cell lines. These results suggest that A-T cells have an altered chromatin structure whereby DNA double-strand breaks are apparently more efficiently converted into chromosome breaks. Four A-T heterozygote cell lines were examined for chromosome damage and repair in the same fashion and all exhibited increased levels of chromosome damage, although the degree of sensitivity was more prominent in G2 phase cells (two-fold higher) than in G1 phase cells (1.5-fold higher than normal controls). These results suggest that A-T heterozygotes also exhibit an altered chromatin structure which impacts on chromosome damage expression. Of interest, A-T cells also exhibited increased chromosome stickiness after irradiation, and telomere regions appeared to be frequently involved. While the molecular basis for preferential telomere involvement is not understood, these results again suggest that structural alterations in the chromatin of A-T cells may play an important role in A-T radiosensitivity.
Department of Clinical Investigation, University of Texas M. D. Anderson Cancer Center, Houston 77030.
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Hittelman
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Pandita
D001260:Ataxia Telangiectasia / Q000235:genetics / Q000503:physiopathology*; D002843:Chromatin / Q000502:physiology*; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D011836:Radiation Tolerance / Q000502:physiology*
D002843:Chromatin