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Radiosensitivity in Nijmegen Breakage Syndrome Cells Is Attributable to a Repair Defect and not Cell Cycle Checkpoint Defects¹

Medical Research Council Cell Mutation Unit, University of Sussex, Falmer, Brighton BN1 9RR, United Kingdom [P-M. G., A. W., E. R., C. F. A., P. A. J.]; UMR1599 Centre National de la Recherche Scientifique, Institut Gustave-Roussy, 94805 Villejuif, France [N. F.]; Institut fuer Humangenetik, Universitaetsklinikum, 39120 Magdeburg, Germany [M. S.]; Laboratory of Genetics, Department of Experimental Therapy, University of Wisconsin, Madison, Wisconsin 53706 [R. S. M., J. P.]; and Royal Free Hospital, Hampstead, London NW3 2PF, United Kingdom [W. P. P.]

Cells derived from Nijmegen Breakage Syndrome (NBS) patients display radiosensitivity and cell cycle checkpoint defects. Here, we examine whether the radiosensitivity of NBS cells is the result of a repair defect or whether it can be attributed to impaired checkpoint arrest. We report a small increased fraction of unrejoined double strand breaks and, more significantly, increased chromosome breaks in noncycling NBS cells at 24 h after irradiation. One of the NBS lines examined (347BR) was atypical in showing a nearly normal checkpoint response. In contrast to the mild checkpoint defect, 347BR displays marked -ray sensitivity similar to that shown by other NBS lines. Thus, the -ray sensitivity correlates with the repair defect rather than impaired checkpoint control. Taken together, the results provide direct evidence for a repair defect in NBS cells and are inconsistent with the suggestion that the radiosensitivity is attributable only to impaired checkpoint arrest. 347BR also displays elevated spontaneous damage that cannot be attributed to impaired G₂-M arrest, suggesting a function of Nbs1 in decreasing or limiting the impact of spontaneously arising double strand breaks.

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