DNA Double-Strand Breaks, p53, and Apoptosis during Lymphomagenesis in scid/scid Mice

Abstract The tumor-suppressing phenotype of p53 is thought to be due to its accumulation in response to DNA damage and resultant cell cycle arrest or apoptosis. scid/scid mice are defective in DNA double-strand break repair due to a mutation in DNA-dependent protein kinase ( DNAPK ). Treatment of scid/scid mice with γ radiation or N -ethyl- N -nitrosourea resulted in ∼86% incidence of T-cell lymphomas, compared with scid/scid mice, suggesting that the types of DNA double-strand break that are unrepaired in these mice are not strongly carcinogenic. To determine whether mutations in DNAPK and p53 interact, we examined mice deficient in both genes. Both scid/scid p53-/- and scid/scid p53+/- mice spontaneously developed lymphomas at shorter latency than did mice with either defect alone. Loss of the wild-type p53 allele was observed in 100% of tumors from scid/scid p53+/- mice, indicating strong selection against p53 . In contrast, p53 was not inactivated in lymphomas from scid/scid p53 +/+ mice. Exposure of these tumor-bearing mice to γ radiation resulted in p53 protein accumulation and high levels of apoptosis in all tumors that were not observed in tumors from scid/scid p53 +/- mice. Thus, there was a bifurcation of molecular pathways to tumorigenesis. When p53 was heterozygous in the germ line, loss of the wild-type allele occurred, and the tumors became apoptosis resistant. When p53 was wild type in the germ line, p53 was not inactivated, and the tumors remained highly apoptosis sensitive.