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, 18 (7), 748-54

Unraveling the Mechanism of BRCA2 in Homologous Recombination


Unraveling the Mechanism of BRCA2 in Homologous Recombination

William K Holloman. Nat Struct Mol Biol.


BRCA2 is the product of a breast cancer susceptibility gene in humans and the founding member of an emerging family of proteins present throughout the eukaryotic domain that serve in homologous recombination. The function of BRCA2 in recombination is to control RAD51, a protein that catalyzes homologous pairing and DNA strand exchange. By physically interacting with both RAD51 and single-stranded DNA, BRCA2 mediates delivery of RAD51 preferentially to sites of single-stranded DNA (ssDNA) exposed as a result of DNA damage or replication problems. Through its action, BRCA2 helps restore and maintain integrity of the genome. This review highlights recent studies on BRCA2 and its orthologs that have begun to illuminate the molecular mechanisms by which these proteins control homologous recombination.


Figure 1
Figure 1. DNA repair by HR
Schematics are shown illustrating how repair of DNA with a DSB or ssDNA gap could initiate by HR. Both pathways begin with invasion of a ssDNA tract (step i or i-a) into a homologous DNA sequence. In DSB repair the D-loop formed after invasion of the ssDNA tail (step ii) is extended by DNA synthesis (step iii) until it can pair with, or capture, the second end through exposed complementary sequence. The 3′ strand of the second end serves as a primer for fill-in synthesis (step iv). Additional processing of the intermediates and several subsequent steps results in a repaired chromosome. In the other pathway, termed post-replication repair, a ssDNA gap generated during DNA replication of a damaged template (step i-a) invades the undamaged homologous sequence present in the sister chromatid (step ii-a). By branch migration through a short tract the 3′ end of the broken strand switches templates (step iii-a) and then serves as primer for fill-in synthesis (step iv-a). After additional steps the intermediate is resolved and repair is completed.
Figure 2
Figure 2. BRCA2 organization and DBD domain structure
(a) BRCA2 is shown schematically with protein interaction motifs and domains identified on top. The acronyms are as described in the text. CTRM is C-terminal RAD51-binding motif. The elements are illustrated as gray and black boxes. The DBD is broken down into the helix-rich domain (hatches) and the three OB folds (ovals). The approximate regions of interaction with the various proteins and DNA discussed are shown underneath. (b) The 800 residue DBD is shown schematically with the helix-rich domain (HD) followed by the OB folds. OB2 and OB3 are packed in tandem while OB1 is packed with OB2 in the opposite orientation. The Tower domain emerges from OB2 and has a three-helix bundle (3HB) on top. ssDNA (black squiggle) interacts with OB2 and OB3. DSS1 (gray squiggle) interacts with HD and OB1 on the opposite face of the domain.

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