IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42830-1.html
   My bibliography  Save this article

Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2

Author

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42830-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-42830-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    2. Youngho Kwon & Heike Rösner & Weixing Zhao & Platon Selemenakis & Zhuoling He & Ajinkya S. Kawale & Jeffrey N. Katz & Cody M. Rogers & Francisco E. Neal & Aida Badamchi Shabestari & Valdemaras Petrosi, 2023. "DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    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.
    4. Weiran Feng & Maria Jasin, 2017. "BRCA2 suppresses replication stress-induced mitotic and G1 abnormalities through homologous recombination," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    5. Luca Pellegrini & David S. Yu & Thomas Lo & Shubha Anand & MiYoung Lee & Tom L. Blundell & Ashok R. Venkitaraman, 2002. "Insights into DNA recombination from the structure of a RAD51–BRCA2 complex," Nature, Nature, vol. 420(6913), pages 287-293, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Youngho Kwon & Heike Rösner & Weixing Zhao & Platon Selemenakis & Zhuoling He & Ajinkya S. Kawale & Jeffrey N. Katz & Cody M. Rogers & Francisco E. Neal & Aida Badamchi Shabestari & Valdemaras Petrosi, 2023. "DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Rohit Prakash & Thomas Sandoval & Florian Morati & Jennifer A. Zagelbaum & Pei-Xin Lim & Travis White & Brett Taylor & Raymond Wang & Emilie C. B. Desclos & Meghan R. Sullivan & Hayley L. Rein & Kara , 2021. "Distinct pathways of homologous recombination controlled by the SWS1–SWSAP1–SPIDR complex," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. John Hilton & Karen Gelmon & Philippe L. Bedard & Dongsheng Tu & Hong Xu & Anna V. Tinker & Rachel Goodwin & Scott A. Laurie & Derek Jonker & Aaron R. Hansen & Zachary W. Veitch & Daniel J. Renouf & L, 2022. "Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Anastasia Hale & Ashna Dhoonmoon & Joshua Straka & Claudia M. Nicolae & George-Lucian Moldovan, 2023. "Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Yan Wang & Binbin Ma & Xiaoxu Liu & Ge Gao & Zhuanzhuan Che & Menghan Fan & Siyan Meng & Xiru Zhao & Rio Sugimura & Hua Cao & Zhongjun Zhou & Jing Xie & Chengqi Lin & Zhuojuan Luo, 2022. "ZFP281-BRCA2 prevents R-loop accumulation during DNA replication," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Yonina R. Murciano-Goroff & Alison M. Schram & Ezra Y. Rosen & Helen Won & Yixiao Gong & Anne Marie Noronha & Yelena Y. Janjigian & Zsofia K. Stadler & Jason C. Chang & Soo-Ryum Yang & Diana Mandelker, 2022. "Reversion mutations in germline BRCA1/2-mutant tumors reveal a BRCA-mediated phenotype in non-canonical histologies," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    7. Domagoj Vugic & Isaac Dumoulin & Charlotte Martin & Anna Minello & Lucia Alvaro-Aranda & Jesus Gomez-Escudero & Rady Chaaban & Rana Lebdy & Catharina Nicolai & Virginie Boucherit & Cyril Ribeyre & Ang, 2023. "Replication gap suppression depends on the double-strand DNA binding activity of BRCA2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    8. Tanay Thakar & Ashna Dhoonmoon & Joshua Straka & Emily M. Schleicher & Claudia M. Nicolae & George-Lucian Moldovan, 2022. "Lagging strand gap suppression connects BRCA-mediated fork protection to nucleosome assembly through PCNA-dependent CAF-1 recycling," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    9. Poonam Roshan & Sahiti Kuppa & Jenna R. Mattice & Vikas Kaushik & Rahul Chadda & Nilisha Pokhrel & Brunda R. Tumala & Aparna Biswas & Brian Bothner & Edwin Antony & Sofia Origanti, 2023. "An Aurora B-RPA signaling axis secures chromosome segregation fidelity," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42830-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.