Restoration
of T Cell specific V(D)J Recombination in DNA-PKcs-/- Mice by
Ionizing Radiation: The Effects on
Survival, Development, and Tumorigenesis
LI Xiao-Ling*, SHEN Shou-Rong,
WANG Sa1, OUYANG Hong-Hai1, LI Gloria C1
( Cancer Research Institute,
Xiang Ya School of Medicine, Central South University, Changsha 410078,
China; 1Memorial Sloan-kettering Cancer Center, New York, NY
10021, USA )
Abstract
DNA-dependent protein kinase (DNA-PK) is a DNA-activated
nuclearserine/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 γ-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 γ-irradiation. Treatment of
newborn DNA-PKcs-/- mice with sublethal doses of ionizing radiation
restores T cell receptor (TCR)β recombination and T cell maturation. However, radiation does not restore B
cell development. All these mice eventually developed thymic lymphoma. These
observations suggest aninterrelationship 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.
Key words DNA-PKcs; DNA DSB repair; V(D)J
recombination; apoptosis; tumorigenesis
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Fax, 86-731-4805383;
e-mail, [email protected]