A role for topoisomerase II alpha in the formation of radiation-induced chromatid breaks.
Chromatid breaks in cells exposed to low dose irradiation are thought to be initiated by DNA double-strand breaks (DSB), and the frequency of chromatid breaks has been shown to increase in DSB rejoining deficient cells. However, the underlying causes of the wide variation in frequencies of G2 chromatid breaks (or chromatid 'radiosensitivity') in irradiated T-lymphocytes from different normal individuals and cancer cases are as yet unclear. Here we report evidence that topoisomerase II alpha expression level is a factor determining chromatid radiosensitivity. We have exposed the promyelocytic leukaemic cell line (HL60) and two derived variant cell lines (MX1 and MX2) that have acquired resistance to mitoxantrone and low expression of topoisomerase II alpha, to low doses of gamma-radiation and scored the induced chromatid breaks. Chromatid break frequencies were found to be significantly lower in the variant cell lines, compared with their parental HL60 cell line. Rejoining of DSB in the variant cell lines was similar to that in the parental HL60 strain. Our results indicate the indirect involvement of topoisomerase II alpha in the formation of radiation-induced chromatid breaks from DSB, and suggest topoisomerase II alpha as a possible factor in the inter-individual variation in chromatid radiosensitivity.
Terry
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Bute Medical School, Bute Medical Buildings, University of St Andrews, St Andrews KY16 9TS, Scotland, UK.
Riches
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Bryant
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D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002842:Chromatids / Q000528:radiation effects*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D008940:Mitotic Index; D008942:Mitoxantrone / Q000494:pharmacology; D011836:Radiation Tolerance; D012854:Sister Chromatid Exchange / Q000528:radiation effects
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II