Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2

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Joudeh, Luay 
Cobbett, Katie 

jats:titleAbstract</jats:title>jats:pThe BRCA2 tumour suppressor protein preserves genomic integrity via interactions with the DNA-strand exchange RAD51 protein in homology-directed repair. The RAD51-binding TR2 motif at the BRCA2 C-terminus is essential for protection and restart of stalled replication forks. Biochemical evidence shows that TR2 recognises filamentous RAD51, but existing models of TR2 binding to RAD51 lack a structural basis. Here we used cryo-electron microscopy and structure-guided mutagenesis to elucidate the mechanism of TR2 binding to nucleoprotein filaments of human RAD51. We find that TR2 binds across the protomer interface in the filament, acting as a brace for adjacent RAD51 molecules. TR2 targets an acidic-patch motif on human RAD51 that serves as a recruitment hub in fission yeast Rad51 for recombination mediators Rad52 and Rad55-Rad57. Our findings provide a structural rationale for RAD51 filament stabilisation by BRCA2 and reveal a common recruitment mechanism of recombination mediators to the RAD51 filament.</jats:p>


Acknowledgements: We would like to thank Joseph Maman, Tom Blundell and Owen Davies for helpful discussions and advice, Dimitri Chirgadze and staff at the cryoEM Facility of the Department of Biochemistry for help with data collection. This work was funded by Wellcome Trust award 221892/Z/20/Z to L.P. and a BBSRC DTP studentship to R.A.

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Nature Communications
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Springer Science and Business Media LLC
Wellcome Trust (Wellcome) (221892/Z/20/Z)