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Loss of Brca2 and p53 Synergistically Promotes Genomic Instability and Deregulation of T-cell Apoptosis¹

Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2M9 [A. M. Y. C., F. J., M-S. T., B. S., J. P. M., J. K., A. W., A. Y-T., A. E., J. S., R. B., R. H., T. W. M.]; Advanced Medical Discovery Institute, Toronto, Ontario, Canada [A. M. Y. C., B. S., J. P. M., A. W., A. Y-T., A. E., R. H., T. W. M.]; Department of Physiology, Faculty of Medicine, National University of Singapore, 117597 Singapore [M. P. H.]; The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, Tokyo 160-8582, Japan [A. H.]; and Akita University School of Medicine, Department of Biochemistry, Akita 010-8543, Japan [A. S.]

BRCA2 is a breast cancer susceptibility gene of which the product is thought to be involved in monitoring genome integrity and cell cycle progression. Brca2-null mice have a defect in embryonic cellular proliferation and die in utero. Here we report the generation of T-cell lineage-specific Brca2-deficient (tBrca2^-/-) mice using the Cre-loxP system. Mice with a flanked by loxP allele of Brca2 were crossed to transgenic mice bearing Cre recombinase driven by the T cell-specific promoter Lck. Thymic cellularity and distribution of subset populations were normal in tBrca2^-/- mutants. Thymocytes from tBrca2^-/- mice underwent normal apoptosis in response to a variety of stimuli, and activated tBrca2^-/- T cells had normal proliferative capacity. tBrca2^-/- T cells were more likely than wild-type cells to undergo spontaneous apoptosis, but apoptosed normally in response to restimulation or DNA-damaging stress signals. Examination of metaphase spreads of tBrca2^-/- T cells revealed that the chromosomes often exhibited aberrations such as breaks and tri-radial structures. The level of chromosomal abnormalities was enhanced in T cells from tBrca2^-/-; p53^-/- double-mutant mice. However, tBrca2^-/-; p53^-/- T cells did not show the enhanced level of spontaneous apoptosis demonstrated by tBrca2^-/- T cells, a difference that likely accounts for an increase in cell number and ³[H]thymidine incorporation of double-mutant T cells in culture compared with either single mutant. Despite this increased T-cell number, the onset of T-cell lymphomas was only marginally accelerated in tBrca2^-/-; p53^-/- mice compared with p53^-/- mice. Our results support a role for Brca2 in repairing spontaneous DNA lesions, and suggest that loss of Brca2 enhances the susceptibility of mouse T-lineage cells to chromosomal aberrations and deregulation of apoptosis in the absence of p53.

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