title: Loss of Brca2 and p53 synergistically promotes genomic instability and deregulation of T-cell apoptosis.
abstract: 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.
authors.affiliation: Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Ontario, Canada M5G 2M9.
authors.forename: Alison M Y
authors.initials: AM
authors.lastname: Cheung
authors.forename: M Prakash
authors.initials: MP
authors.lastname: Hande
authors.forename: Farid
authors.initials: F
authors.lastname: Jalali
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Brian
authors.initials: B
authors.lastname: Skinnider
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: J Peter
authors.initials: JP
authors.lastname: McPherson
authors.forename: Jana
authors.initials: J
authors.lastname: Karaskova
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Annick
authors.initials: A
authors.lastname: You-Ten
authors.forename: Andrew
authors.initials: A
authors.lastname: Elia
authors.forename: Jeremy
authors.initials: J
authors.lastname: Squire
authors.forename: Rob
authors.initials: R
authors.lastname: Bristow
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D019070:Cell Lineage; D002869:Chromosome Aberrations; D004249:DNA Damage; D024522:Genes, BRCA2; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology
chemical_list: D024682:BRCA2 Protein; D016159:Tumor Suppressor Protein p53