Restoration of T cell-specific V(D)J recombination in DNA-PKcs(-/-) mice by ionizing radiation: The effects on survival, development, and tumorigenesis.
DNA-dependent protein kinase (DNA-PK) is a DNA-activated nuclear serine/threonine protein kinase. DNA-PK consists of a heterodimeric Ku subunit (composed of a 70 and 86 kD subunit) which binds DNA ends and targets the catalytic subunit DNA-PKcs to DNA strand breaks. DNA-PK plays a major role in the repair of double-strand breaks (DSB) induced in DNA after exposure to ionizing radiation. To better understand the nature of DNA repair defect associated with DNA-PKcs deficiency, we have established DNA-PKcs(-/-) mouse embryo fibroblast cell lines and DNA-PKcs(-/-) null mice, and investigated the response of these mutant cells and mice to DNA damage. DNA-PKcs(-/-) cells are hypersensitive to gamma-irradiation, as evidenced by their low survival as assayed by colony formation efficiencies. Consistent with the radiation hypersensitive phenotype of the cell lines, DNA-PKcs(-/-) mice also display an extreme radiosensitivity, characterized by enhanced mortality after gamma-irradiation. Treatment of newborn DNA-PKcs(-/-) mice with sublethal doses of ionizing radiation restores T cell receptor (TCR) beta recombination and T cell maturation. However, radiation does not restore B cell development. All these mice eventually developed thymic lymphoma. These observations suggest an interrelationship between DSB repair, V(D)J recombination and lymphomagenesis, and provide an in vivo model to elucidate the critical pathways between the regulation of DNA DSB repair, V(D)J recombination, and the molecular mechanism of lymphoid neoplasia.
Li
Xiao-Ling
XL
Cancer Research Institute, Xiang Ya School of Medicine, Central South University, Changsha 410078, China. xlli2000@yahoo.com
Shen
Shou-Rong
SR
Wang
Sa
S
Ouyang
Hong-Hai
HH
Li
Gloria C
GC
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000528:radiation effects; D001402:B-Lymphocytes / Q000166:cytology / Q000528:radiation effects; D002455:Cell Division / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics / Q000528:radiation effects*; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008223:Lymphoma / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016019:Survival Analysis; D013953:Thymus Neoplasms / Q000209:etiology / Q000235:genetics
D004268:DNA-Binding Proteins; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases