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Irradiation-Induced Rescue of Thymocyte Differentiation and V(D)J Recombination in Mice Lacking the Catalytic Subunit of DNA-Dependent Protein Kinase¹

Chiyu Wang^*, Molly A. Bogue^*, Anthony P. Nguyen^* and David B. Roth^*,,2

^* Department of Microbiology and Immunology and Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030

Scid mice express a truncated form of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) and are unable to properly rearrange their Ig and TCR genes, resulting in a severe combined immunodeficiency that is characterized by arrested differentiation of B and T lymphocytes. Treatment of scid mice with low doses of gamma irradiation rescues rearrangements at several TCR loci and promotes limited thymocyte differentiation. The machinery responsible for sensing DNA damage and the mechanism by which irradiation compensates for the scid defect in TCR recombination remain unknown. Because DNA-PKcs is present in scid thymocytes, it may mediate some or all of the irradiation effects. To test this hypothesis, we examined the effects of irradiation on DNA-PKcs-deficient (slip) mice. Our data provide the first evidence that DNA-PKcs is not required for limited rescue of thymocyte differentiation or TCR rearrangements.

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