Abstract
Around 50% of all familial breast and ovarian cancers are due to mutations in BRCA1 and BRCA2. Germline mutations in the BRCA2 gene are associated with an increased susceptibility to breast cancer (in both males and females) and they also confer an increased risk of early onset ovarian, prostate, and pancreatic cancer. The biological function of BRCA2 in the cell is still uncertain, although there is increasing evidence for a role in the repair of DNA by homologous recombination. BRCA2 and RAD51 (a homolog of the baterial recombination protein RecA) both co-localise to nuclear foci thought to be sites of DNA damage and repair and these nuclear foci fail to form in BRCA2 deficient cells. Loss of BRCA2 leads to error prone repair of double strand DNA breaks and in dividing cells can lead to chromosomal abberations and loss of genetic information. Compelling evidence of a more direct role for BRCA2 in DNA repair is provided by two recent studies investigating some of the protein's structural interactions.
Highlights
In an exceptional publication in Science [1], Yang and colleagues demonstrate the crystal structure of the 800residue carboxyl-terminal domain of BRCA2 that lies beyond the sequence of highly conserved BRC motifs
This paper reports for the first time the crystal structure of the complex between a BRC repeat and the catalytic domain of RAD51
The BRC repeat is found to mimic a motif in RAD51 that serves as an interface between adjacent RAD51 monomers
Summary
Around 50% of all familial breast and ovarian cancers are due to mutations in BRCA1 and BRCA2. In an exceptional publication in Science [1], Yang and colleagues demonstrate the crystal structure of the 800residue carboxyl-terminal domain of BRCA2 that lies beyond the sequence of highly conserved BRC motifs (sets of amino acid repeats in the centre of BRCA2). This carboxyl-terminal region is likely to play an important role in the tumour suppressor function of BRCA2 as it corresponds to the most conserved portion of BRCA2 across different species and contains 27% of tumour-derived missense mutations.
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