HYPERSENSITIVITY OF KU80-DEFICIENT CELL-LINES AND MICE TO DNA-DAMAGE - THE EFFECTS OF IONIZING-RADIATION ON GROWTH, SURVIVAL, AND DEVELOPMENT

We recently have shown that mice deficient for the 86-kDa component (K u80) of the DNA-dependent protein kinase exhibit growth retardation an d a profound deficiency in V(D)J (variable, diversity, and joining) re combination. These defects may be related to abnormalities in DNA meta bolism that arise from the inability of Ku80 mutant cells to process D NA double-strand breaks. To further characterize the rot of Ku80 in DN A double-strand break repair; we have generated embryonic stem cells a nd pre-B cells and examined their response to ionizing radiation. Ku80 (-/-) embryonic stem cells are more sensitive than controls to gamma-i rradiation, and pre-B cells derived from Ku80 mutant mice display enha nced spontaneous and gamma-ray-induced apoptosis, We then determined t he effects of ionizing radiation on the survival, growth, and lymphocy te development in Ku80-deficient mice, Ku80(-/-) mice display a hypers ensitivity to gamma-irradiation, characterized by toss of hair pigment ation, severe injury to the gastrointestinal tract, and enhanced morta lity. Exposure of newborn Ku80(-/-) mice to sublethal doses of ionizin g radiation enhances their growth retardation and results in the induc tion of T cell-specific differentiation, However, unlike severe combin ed immunodeficient mice, radiation-induced T cell development in Ku80( -/-) mice is not accompanied by extensive thymocyte proliferation. The response of Ku80-deficient: cell lines and mice to DNA-damaging agent s provides important insights into the role of Ku80 in growth regulati on, lymphocyte development, acid DNA repair.