Mutagenesis in vivo in T cells of p21-deficient mice.

Mice that are deficient in p53 exhibit an early onset of multiple types of tumors, especially thymic lymphoma. However, it remains unclear to what extent each of the p53-regulated pathways exerts its tumor suppressor activity. p21(Cip1/Waf1), acting down stream of p53, is a major G1/S checkpoint protein that restricts cell cycle progression into S phase in the presence of DNA damage. While at old ages p21-/- mice have a higher incidence of many types of tumors than p21+/+ mice, they are more resistant to thymic lymphomagenesis. In this study, we characterized mutagenesis in vivo in T cells of p21-deficient mice, using loss of heterozygosity (LOH) at Aprt locus as an indicator. We found that the spontaneous Aprt mutant frequency in T cells of p21-/- mice is lower than that in p21+/+ mice. The mutational spectra, however, are similar, with mitotic recombination being the predominant pathway. In contrast to the remarkable induction of LOH events in T cells of p53-/- mice exposed to X-rays, LOH in T cells of p21-/- mice is not significantly induced by X-rays. Correspondingly, lymphoid cells of p21-/- mice are more sensitive to IR-induced apoptosis than those of p21+/+ mice, in contrast to the radioresistance of p53-deficient lymphocytes. Reduction in mutation load in T cell lineages may contribute to the suppression of thymic lymphomagenesis in p21-/- mice.