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Ku Affects the CHK1-dependent G₂ Checkpoint after Ionizing Radiation¹

Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [X. W., Y. W.]; Departments of Radiation Oncology and Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [G. C. L.]; and Institute of Medical Radiation Biology, University of Essen Medical School, 45122 Essen, Germany [G. I.]

There are two major pathways for repairing DNA double strand breaks in mammalian cells: nonhomologous end joining (NHEJ) and homologous recombination repair (HRR). The nonhomologous end joining repair is deficient in cells without Ku, whereas HRR is highly efficient in such cells compared with their wild-type counterparts. The mechanism remains unclear. We reported previously that Ku80^-/- cells show a stronger ATM-dependent S-phase checkpoint response than Ku80^+/+ cells after ionizing radiation (IR; X-Y. Zhou et al., Oncogene, 21:6377–6381, 2002). We report in this study that Ku80^-/- cells also show a much stronger G₂ accumulation than Ku80^+/+ cells after IR. The stronger G₂ checkpoint response in Ku80^-/- cells is ATM independent but is accompanied with a higher activity of CHK1 kinase. Treatment with Chk1 antisense oligonucleotide abolishes the stronger G₂ checkpoint response and sensitizes Ku80^-/- cells to IR. These data indicate that the stronger G₂ checkpoint response shown in Ku80^-/- cells is CHK1 dependent and suggest that the CHK1-dependent checkpoint response contributes to the highly efficient HRR in such cells.

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