Accumulation of recombinant chromosomes and low fidelity of transmission of chromosome X DNA markers in gamma-ray-induced lymphomas lacking p53

F-1 offspring of male MSM male mice with a p53-deficient (knockout) allele and normal female BALB/c mice were backcrossed with MSM mice to produce N-2 mice. Female F-1 and N-2 mice were irradiated with gamma-radiation, and th ymic lymphomas were obtained from 69 F-1 and 82 N-2 mice heterozygous for X chromosome markers. Of these 151 mice, 91 carried a p53-deficient allele. These lymphomas were analyzed for allelic loss by using four marker loci di stributed on X chromosome to assess the stability of the inactive X chromos ome, which contributes little to cellular functions. Twenty lymphomas showe d allelic loss of all four loci, suggesting loss of a whole inactive X chro mosome due to mitotic nondisjunction, whereas 24 lost only a part of an X c hromosome, as a result of somatic recombination. The p53 status of the lymp homas was determined by genotyping and allelic loss analysis: 53 had retain ed two wild-type p53 alleles, suggesting normal function; 69 had lost both alleles, indicating loss of function; and the remaining 29 had at least one wild-type p53 allele, so their p53 status was unclear. Compilation of thes e two data revealed one nondisjunction-type change and five recombination-t ype mutations on X chromosome in 53 lymphomas retaining functional p53. In contrast, 14 and 16 of these alterations, respectively, were observed in 69 lymphomas lacking p53 function. These results suggest that p53 loss signif icantly increases the accumulation of recombinant chromosomes and decreases the fidelity of mitotic chromosome transmission of the X chromosome in gam ma-ray-induced lymphomas. (C) 1999 Wiley-Liss. Inc.