P53 IS REQUIRED FOR BOTH RADIATION-INDUCED DIFFERENTIATION AND RESCUEOF V(D)J REARRANGEMENT IN SCID MOUSE THYMOCYTES

The murine scid mutation affects both V(D)J recombination and DNA repa ir. This mutation has been mapped to the gene encoding the catalytic s ubunit of the DNA-dependent protein kinase (DNA-PK), which is activate d by DNA damage in normal cells. In scid mice, antigen receptor gene r earrangements are initiated normally, but impaired joining of coding e nds prevents assembly of functional receptor genes, resulting in arres t of B- and T-cell development. Others have shown that exposure of sci d mice to genotoxic agents such as gamma-irradiation rescues rearrange ment at the T-cell receptor (TCR) beta locus and promotes thymocyte de velopment. Here we demonstrate that irradiation rescues rearrangements at multiple TCR loci, suggesting a general effect on the recombinatio n mechanism. Furthermore, our data show that p53 is required for irrad iation-mediated rescue of both thymocyte development and V(D)J recombi nation. 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, p erhaps by inducing p53-dependent DNA damage response pathways.