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Spatiotemporal dynamics of homologous recombination repair at single collapsed replication forks

Author

Listed:
  • Donna R. Whelan

    (New York University School of Medicine
    La Trobe University)

  • Wei Ting C. Lee

    (New York University School of Medicine)

  • Yandong Yin

    (New York University School of Medicine)

  • Dylan M. Ofri

    (New York University School of Medicine)

  • Keria Bermudez-Hernandez

    (New York University School of Medicine)

  • Sarah Keegan

    (New York University School of Medicine)

  • David Fenyo

    (New York University School of Medicine)

  • Eli Rothenberg

    (New York University School of Medicine)

Abstract

Homologous recombination (HR) is a crucial pathway for the repair of DNA double-strand breaks. BRCA1/2 breast cancer proteins are key players in HR via their mediation of RAD51 nucleofilament formation and function; however, their individual roles and crosstalk in vivo are unknown. Here we use super-resolution (SR) imaging to map the spatiotemporal kinetics of HR proteins, revealing the interdependent relationships that govern the dynamic interplay and progression of repair events. We show that initial single-stranded DNA/RAD51 nucleofilament formation is mediated by RAD52 or, in the absence of RAD52, by BRCA2. In contrast, only BRCA2 can orchestrate later RAD51 recombinase activity during homology search and resolution. Furthermore, we establish that upstream BRCA1 activity is critical for BRCA2 function. Our analyses reveal the underlying epistatic landscape of RAD51 functional dependence on RAD52, BRCA1, and BRCA2 during HR and explain the phenotypic similarity of diseases associated with mutations in these proteins.

Suggested Citation

  • Donna R. Whelan & Wei Ting C. Lee & Yandong Yin & Dylan M. Ofri & Keria Bermudez-Hernandez & Sarah Keegan & David Fenyo & Eli Rothenberg, 2018. "Spatiotemporal dynamics of homologous recombination repair at single collapsed replication forks," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06435-3
    DOI: 10.1038/s41467-018-06435-3
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    Cited by:

    1. Kate E. Coleman & Yandong Yin & Sarah Kit Leng Lui & Sarah Keegan & David Fenyo & Duncan J. Smith & Eli Rothenberg & Tony T. Huang, 2022. "USP1-trapping lesions as a source of DNA replication stress and genomic instability," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    3. Liana Goehring & Sarah Keegan & Sudipta Lahiri & Wenxin Xia & Michael Kong & Judit Jimenez-Sainz & Dipika Gupta & Ronny Drapkin & Ryan B. Jensen & Duncan J. Smith & Eli Rothenberg & David Fenyö & Tony, 2024. "Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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