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Checkpoint Abrogation in G₂ Compromises Repair of Chromosomal Breaks in Ataxia Telangiectasia Cells

¹ Institute of Nuclear Technology and Radiation Protection, National Centre for Scientific Research "Demokritos," Aghia Paraskevi Attikis, Athens, Greece and ² Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Essen, Germany

Requests for reprints: Gabriel E. Pantelias, Institute of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research "Demokritos," Patriarchou Grigoriou and Neapoleos Strs., 15310 Aghia Paraskevi Attikis, Athens, Greece. Phone: 30-210-650-3848; Fax: 30-210-654-3526; E-mail: gabriel{at}ipta.demokritos.gr or George Iliakis, Medical Radiation Biology, University of Duisburg-Essen Medical School, Hufelandstr. 55, 45122 Essen, Germany. Phone: 49-201-723-4152 or 4153; Fax: 49-201-723-5966; E-mail: georg.iliakis{at}medizin.uni-essen.de.

Checkpoint abrogation in G₂ compromises repair of DNA double-strand breaks (DSB) and confers enhanced G₂ chromosomal radiosensitivity in ataxia telangiectasia (AT) cells. To directly test this hypothesis, we combined calyculin A–induced premature chromosome condensation with conventional cytogenetics to evaluate chromosome damage before and after the G₂ checkpoint in irradiated primary AT and normal human lymphocytes and their lymphoblastoid derivatives. Direct analysis of radiation damage in G₂ by premature chromosome condensation reveals practically indistinguishable levels of chromosomal breaks in AT and normal cells. Yet a 4-fold increase in metaphase chromosome damage is observed in AT cells as compared with normal cells which, in contrast to AT cells, exhibit a strong G₂ arrest manifest as an abrupt reduction in the mitotic index. Thus, an active checkpoint facilitates repair of chromosomal breaks in normal cells. Treatment with caffeine that abrogates the G₂ checkpoint without significantly affecting DSB rejoining increases metaphase chromosome damage of normal cells to the AT level but leaves unchanged interphase chromosome damage in G₂. Caffeine has no effect on any of these end points in AT cells. These observations represent the first direct evidence that the G₂ checkpoint facilitates repair of chromosome damage, presumably by supporting repair of DNA DSBs. Failure to arrest will lead to chromatin condensation and conversion of unrepaired DNA DSBs to chromosomal breaks during G₂-to-M phase transition. (Cancer Res 2005; 65(24): 11292-6)

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