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Review
, 3 (5), 294-8

BRCA2 and Homologous Recombination

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Review

BRCA2 and Homologous Recombination

B J Orelli et al. Breast Cancer Res.

Abstract

Two recent papers provide new evidence relevant to the role of the breast cancer susceptibility gene BRCA2 in DNA repair. Moynahan et al provide genetic data indicating a requirement for BRCA2 in homology-dependent (recombinational) repair of DNA double-strand breaks. The second paper, by Davies et al, begins to address the mechanism through which BRCA2 makes its contribution to recombinational repair. BRCA2 appears to function in recombination via interactions with the major eukaryotic recombinase RAD51 [1,2,3]. We briefly review the context in which the two studies were carried out, we comment on the results presented, and we discuss models designed to account for the role of BRCA2 in RAD51-mediated repair.

Figures

Figure 1
Figure 1
Recombination substrates used for assaying homology-directed repair. Cutting at the I-SceI site within the mutant GFP (SceGFP) results in a double-strand break that can be repaired through homologous gene conversion using a 3'-truncated copy of GFP as sequence donor. The mechanism results in the formation of a functional copy of the GFP gene. The model shown assumes gene conversion occurs via the synthesis-dependent annealing mechanism.
Figure 2
Figure 2
Potential roles of BRCA2 in promoting assembly of Rad51 at sites of DNA damage. Chromosomal DNA is shown as pairs of straight lines, Rad51 as open circles, and BRCA2 as grey bars. (a) Prevention of nonproductive DNA interactions. BRCA2–Rad51 interaction is proposed to suppress RAD51–BRCA2 interactions until DNA damage is present. When damage occurs, Rad51 is recruited to damaged sites where is polymerizes into nucleoprotein filaments. In this model, BRCA2 is not required for assembly of functional complexes at damaged sites, only to prevent a substantial fraction of Rad51 from being sequestered in a nonfunctional form. In a BRCA2-defective cell, mutant Rad51 becomes associated with DNA at random sites and is therefore not readily recruited to sites of damage. (b) Positive regulation. BRCA2 is proposed to be required for Rad51 to assemble into functional recombinational repair complexes at sites of damage. In BRCA-defective cells, Rad51 fails to associate with sites of damage due to lack of an assembly factor.

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References

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