ABSTRACT
BRCA2 function was investigated using murine models. A mutation in Brca2 was introduced into the germline by homologous recombination in transfected embryonic stem cells. A PGK-neo cassette was introduced into exon 11 of Brca2 that interrupts the open reading frame of the mouse protein. There had been several previous reports describing early embryonic lethality of homozygous mutations in Brca2 null mice. However, in this case some of the homozygous Brca2-/-mutant mice survived to adulthood. Those that did survive had a wide range of defects, including small size, absence of germ cells and the development of lethal thymic lymphomas, which originate almost entirely from the immature double-positive thymocyte population. In addition, fibroblasts cultured from Brca2-/-embryos had a defect in proliferation in culture associated with the accumulation of p53 and p21Wafl/CIP1, which are known to mediate cell cycle arrest and are upregulated in response to DNA damage.
