p53 is required for both radiation-induced differentiation and rescue of V(D)J rearrangement in scid mouse thymocytes.
The murine scid mutation affects both V(D)J recombination and DNA repair. This mutation has been mapped to the gene encoding the catalytic subunit of the DNA-dependent protein kinase (DNA-PK), which is activated by DNA damage in normal cells. In scid mice, antigen receptor gene rearrangements are initiated normally, but impaired joining of coding ends prevents assembly of functional receptor genes, resulting in arrest of B- and T-cell development. Others have shown that exposure of scid mice to genotoxic agents such as gamma-irradiation rescues rearrangement at the T-cell receptor (TCR) beta locus and promotes thymocyte development. Here we demonstrate that irradiation rescues rearrangements at multiple TCR loci, suggesting a general effect on the recombination mechanism. Furthermore, our data show that p53 is required for irradiation-mediated rescue of both thymocyte development and V(D)J recombination. We also find that thymocyte proliferation and differentiation in the absence of DNA damage do not require p53 and are not sufficient to rescue V(D)J recombination. These results suggest that exposure to ionizing radiation facilitates a partial bypass of the scid defect, perhaps by inducing p53-dependent DNA damage response pathways.
Bogue
M A
MA
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Zhu
C
C
Aguilar-Cordova
E
E
Donehower
L A
LA
Roth
D B
DB
D000818:Animals; D001483:Base Sequence; D017252:CD3 Complex; D002454:Cell Differentiation / Q000528:radiation effects; D005720:Gamma Rays; D015329:Gene Rearrangement, T-Lymphocyte / Q000528:radiation effects*; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / Q000528:radiation effects; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000528:radiation effects; D008213:Lymphocyte Activation / Q000528:radiation effects; D051379:Mice; D016513:Mice, SCID; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011995:Recombination, Genetic / Q000528:radiation effects*; D013601:T-Lymphocytes / Q000528:radiation effects*; D013950:Thymus Gland / Q000166:cytology / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D017252:CD3 Complex; D016159:Tumor Suppressor Protein p53