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Honghai Ouyang^*, Andre Nussenzweig^*, Akihiro Kurimasa, Vera da Costa Soares^*, Xiaoling Li^*, Carlos Cordon-Cardo^*, Wen-hui Li, Nge Cheong, Michel Nussenzweig^||, George Iliakis, David J. Chen, and Gloria C. Li^*

From the ^* Department of Medical Physics and Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, 10021; Los Alamos National Laboratory, Los Alamos, New Mexico 87545; Thomas Jefferson University, Philadelphia, Pennsylvania 19107; ^|| Rockefeller University, New York, 10021

Ku is a complex of two proteins, Ku70 and Ku80, and functions as a heterodimer to bind DNA double-strand breaks (DSB) and activate DNA-dependent protein kinase. The role of the Ku70 subunit in DNA DSB repair, hypersensitivity to ionizing radiation, and V(D)J recombination was examined in mice that lack Ku70 (Ku70^–/–). Like Ku80^–/– mice, Ku70^–/– mice showed a profound deficiency in DNA DSB repair and were proportional dwarfs. Surprisingly, in contrast to Ku80^–/– mice in which both T and B lymphocyte development were arrested at an early stage, lack of Ku70 was compatible with T cell receptor gene recombination and the development of mature CD4⁺CD8^– and CD4^–CD8⁺ T cells. Our data shows, for the first time, that Ku70 plays an essential role in DNA DSB repair, but is not required for TCR V(D)J recombination. These results suggest that distinct but overlapping repair pathways may mediate DNA DSB repair and V(D)J recombination.

The work was supported in part by National Institutes of Health grants CA-31397 and CA-56909 (to G.C. Li), CA-42026 (to G. Iliakis), CA-50519 (to D.J. Chen), and Department of Energy Office of Health and Environmental Research (to D.J. Chen). A. Nussenzweig is a research fellow supported by National Institutes of Health training grant CA61801 and M. Nussenzweig is an associate investigator in the Howard Hughes Medical Institute.

¹ Abbreviations used in this paper: AFIGE, asymmetric field inversion gel electrophoresis; CFU-GM, granulocyte/macrophage CFUs; DNA-PK, DNA-dependent protein kinase; DSB, double-strand break, ES, embryonic stem; Gy, Gray; IR, ionizing radiation; IVS, intervening sequence; SP, single-positive.

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