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Insights into DNA recombination from the structure of a RAD51–BRCA2 complex

Abstract

The breast cancer susceptibility protein BRCA2 controls the function of RAD51, a recombinase enzyme, in pathways for DNA repair by homologous recombination. We report here the structure of a complex between an evolutionarily conserved sequence in BRCA2 (the BRC repeat) and the RecA-homology domain of RAD51. The BRC repeat mimics a motif in RAD51 that serves as an interface for oligomerization between individual RAD51 monomers, thus enabling BRCA2 to control the assembly of the RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. The RAD51 oligomerization motif is highly conserved among RecA-like recombinases, highlighting a common evolutionary origin for the mechanism of nucleoprotein filament formation, mirrored in the BRC repeat. Cancer-associated mutations that affect the BRC repeat disrupt its predicted interaction with RAD51, yielding structural insight into mechanisms for cancer susceptibility.

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Figure 1: The RAD51–BRC4 complex.
Figure 2: The RAD51–BRC4 interface.
Figure 3: BRCA2 inhibits RAD51 filament formation.
Figure 4: Mutational analysis of RAD51's self-association and BRCA2 binding.
Figure 5: Mutational analysis of RAD51 focus formation.

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Acknowledgements

We thank A. Gupta for early work on the purification of the RAD51–BRCA2 complex; A. Thompson for technical assistance at the ESRF beamline ID29; M. Symmons for help with the figures; and R. Laskey for comments on this manuscript. This research was supported in the laboratory of T.L.B. by the Wellcome Trust, and in the laboratory of A.R.V. by the Medical Research Council and Cancer Research UK.

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Correspondence to Ashok R. Venkitaraman.

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Pellegrini, L., Yu, D., Lo, T. et al. Insights into DNA recombination from the structure of a RAD51–BRCA2 complex. Nature 420, 287–293 (2002). https://doi.org/10.1038/nature01230

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