Embryonic lethality in the Brca1-1700T mouse model suggests inhibition of p53-dependent pathways

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The vast majority of mutations found in the human BRCA1 gene predict expression of a truncated protein, which may retain one or more functional domains. To test the possibility that truncated BRCA1 proteins might have a dominant effect on wild-type BRCA1 or other proteins, we generated a targeted mouse model, designated Brca1 ^1700T, in which a neomycin resistance gene is inserted in exon 20 of the murine Brca1 gene. This mutation is predicted to result in expression of a mutant Brca1 protein which will not encompass the last BRCT repeat, most likely resulting in disruption of the p53-specific transactivation domain. RT-PCR analysis confirmed that the mutant transcript is expressed.

Mice heterozygous for this mutation do not show a predisposition to tumorigenesis. Also γ -radiation does not have a significant effect on these mice. As has been reported for the other Brca1 mouse models, homozygosity for this mutation is embryonic lethal. However, the developmental stage at which lethality occurs differs from the other models. Preliminary results indicate that homozygous Brca1 ^1700Tembryos can reach headfold stage, although not before 9.5 dpc, after which further development is blocked or lethally impaired.

The observed embryonic phenotype resembles the one found in compound Brca1^-/-Tp53^-/- embryos. This might suggest that in the Brca1 ^1700T mouse model embryonic lethality is caused by a combination of disturbed dsDNA break repair and an impaired p53-dependent response to the resulting genetic instability. Possibly, p53 binds to the mutant Brca1 protein, which still contains the p53-binding domain. However, since the C-terminal p53 transactivation domain is likely to be disturbed, this interaction might result in p53 being blocked in an inactive complex. Recently, p53 was shown to be able to lead to tumorigenesis by haploin-sufficiency. The latter observation suggests that even a partial sequestering of p53 by a mutant Brca1 protein may result in a cellular phenotype.