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Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2

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Listed:
  • Robert Appleby

    (University of Cambridge)

  • Luay Joudeh

    (University of Cambridge)

  • Katie Cobbett

    (University of Cambridge)

  • Luca Pellegrini

    (University of Cambridge)

Abstract

The 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.

Suggested Citation

  • Robert Appleby & Luay Joudeh & Katie Cobbett & Luca Pellegrini, 2023. "Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42830-1
    DOI: 10.1038/s41467-023-42830-1
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    References listed on IDEAS

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    1. Fumiko Esashi & Nicole Christ & Julian Gannon & Yilun Liu & Tim Hunt & Maria Jasin & Stephen C. West, 2005. "CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair," Nature, Nature, vol. 434(7033), pages 598-604, March.
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    3. Stacey L. Edwards & Rachel Brough & Christopher J. Lord & Rachael Natrajan & Radost Vatcheva & Douglas A. Levine & Jeff Boyd & Jorge S. Reis-Filho & Alan Ashworth, 2008. "Resistance to therapy caused by intragenic deletion in BRCA2," Nature, Nature, vol. 451(7182), pages 1111-1115, February.
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