Roles of BRCA2 Gene in Homologous Recombination and Genomic Stability
Abstract
The Brca2 tumor suppressor gene is important for maintaining genomic integrity because, at least in part, of a role in homologous recombinational repair. Brca2 is presumed to function in homologous recombination through its interactions with Rad51. Both exon 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 Rad5 i-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 brca2lex1. Mice homozygous for brca2lex1 exhibit a shorter life span compared to control littermates, possibly due to an early onset of cancer and sepsis. No other phenotype was observed in these animals; therefore, the brca2lex1 mutation is less severe than those with larger COOH-terminal truncations that delete some of the BRC motifs. However, at the cellular level, the brca2lex1 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..
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA403331
Entities
People
- David J. Chen
Organizations
- University of California, Berkeley