Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: The effects of ionizing radiation on growth, survival, and development

被引:164
作者
Nussenzweig, A
Sokol, K
Burgman, P
Li, LG
Li, GC
机构
[1] MEM SLOAN KETTERING CANC CTR,DEPT MED PHYS,NEW YORK,NY 10021
[2] MEM SLOAN KETTERING CANC CTR,DEPT RADIAT ONCOL,NEW YORK,NY 10021
[3] ROCKEFELLER UNIV,LAB ANIM RES CTR,NEW YORK,NY 10021
关键词
D O I
10.1073/pnas.94.25.13588
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We recently have shown that mice deficient for the 86-kDa component (Ku80) of the DNA-dependent protein kinase exhibit growth retardation and a profound deficiency in V(D)J (variable, diversity, and joining) recombination. These defects may be related to abnormalities in DNA metabolism that arise from the inability of Ku80 mutant cells to process DNA double-strand breaks. To further characterize the rot of Ku80 in DNA double-strand break repair; we have generated embryonic stem cells and pre-B cells and examined their response to ionizing radiation. Ku80(-/-) embryonic stem cells are more sensitive than controls to gamma-irradiation, and pre-B cells derived from Ku80 mutant mice display enhanced spontaneous and gamma-ray-induced apoptosis, We then determined the effects of ionizing radiation on the survival, growth, and lymphocyte development in Ku80-deficient mice, Ku80(-/-) mice display a hypersensitivity to gamma-irradiation, characterized by toss of hair pigmentation, severe injury to the gastrointestinal tract, and enhanced mortality. Exposure of newborn Ku80(-/-) mice to sublethal doses of ionizing radiation enhances their growth retardation and results in the induction of T cell-specific differentiation, However, unlike severe combined 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 agents provides important insights into the role of Ku80 in growth regulation, lymphocyte development, acid DNA repair.
引用
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页码:13588 / 13593
页数:6
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