FEMALE EMBRYONIC LETHALITY IN MICE NULLIZYGOUS FOR BOTH MSH2 AND P53

The mutator hypothesis of tumorigenesis suggests that loss of chromoso mal stability or maintenance functions results in elevated mutation ra tes, leading to the accumulation of the numerous mutations required fo r multistep carcinogenesis' The human DNA mismatch repair (MMR) genes are highly conserved homologues of the Escherichia coli MutHLS system, which contribute to genomic stability by surveillance and repair of r eplication misincorporation errors and exogenous DNA damage(2), Mutati ons in one of these MMR genes, hMSH2, account for about half of all ca ses of genetically linked hereditary non-polyposis colorectal cancer(3 ,4). Loss of function of p53 has also been proposed to increase cellul ar hypermutability, thereby accelerating carcinogenesis(5), although a clear role for p53 in genomic instability remains controversial(2). p 53 is mutated frequently in a wide range of human cancers, including c olonic tumours(6), Both Msh2- and p53-targeted knockout mice are viabl e and susceptible to cancer(7-11). Here we demonstrate that combined M sh(2) and p53 ablation (Msh2(-/-)p53(-/-)) results in developmental ar rest of all female embryos at 9.5 days. In contrast, male Msh2(-/-)p53 (-/-) mice are viable, but succumb to tumours significantly earlier (t (1/2) is 73 days) than either Msh2(-/-) or p53(-/-) littermates. Furth ermore, the frequency of microsatellite instability (MSI) in tumours f rom Msh2(-/-)p53(-/-) mice is not significantly different than in Msh2 (-/-) mice. Synergism in tumorigenesis and independent segregation of the MSI phenotype suggest that Msh2 and p53 are not genetically epista tic.