Roles of BRCA2 Gene in Homologous Recombination and Genomic Stability

摘要

Brca2 is a major breast cancer susceptibility gene. Recent evidence has indicated that Brca2 is important for maintaining genomic integrity because of a role in homologous recombinational repair (HRR). Brca2 is presumed to function in homologous recombination through its interactions with Rad51. Both exons 11 and 27 of Brca2 code for domains that interact with Rad51; exon 11 codes for eight BRC motifs, while exon 27 codes for a single, distinct interaction domain. Deletion of all the Rad51-interacting domains causes early embryonic lethality in mice. A less severe phenotype is seen in mice with deletions that preserve some, but not all, of the BRC motifs. These mice can survive past weaning, but are runted, infertile, and die very young from cancer. Cells derived from such mice are hypersensitive to some genotoxic agents and exhibit chromosomal instability. Here we present analysis of mice and cells with a deletion of the single Rad51-interacting region encoded by exon 27 (all the BRC motifs are preserved). This mutation is called Brca2(sup lex1). Mice homozygous for Brca2(sup lex1) exhibit a shorter life span compared to control litter mates, possibly due to an early onset of cancer and sepsis. No other phenotype was observed in these animals; therefore, the Brca2(sup lex1) mutation is less severe than those with larger COOH-terminal truncations that delete some of the BRC motifs. However, at the cellular level, the Brca2(sup lex1) mutation causes reduced viability, extreme sensitivity to the DNA interstrand cross- linking agent mitomycin C, and gross chromosomal instability, much like the more severe truncations. These results confirm that the extreme COOH-terminal region encoded by exon 27, though not essential to organismal viability, is important for the function of Brca2 at the cellular level, most probably because it is required for a fully functional interaction between Brca2 and Rad51.