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The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA

Author

Listed:
  • Sarah R. Hengel

    (UPMC-Hillman Cancer Center
    Department of Biology)

  • Katherine G. Oppenheimer

    (UPMC-Hillman Cancer Center)

  • Chelsea M. Smith

    (UPMC-Hillman Cancer Center
    Department of Pathology and Laboratory Medicine)

  • Matthew A. Schaich

    (UPMC-Hillman Cancer Center)

  • Hayley L. Rein

    (UPMC-Hillman Cancer Center)

  • Julieta Martino

    (UPMC-Hillman Cancer Center
    GeneDx)

  • Kristie E. Darrah

    (Department of Biochemistry and Biophysics)

  • Maggie Witham

    (Department of Biology)

  • Oluchi C. Ezekwenna

    (Department of Biology)

  • Kyle R. Burton

    (Department of Biology)

  • Bennett Houten

    (UPMC-Hillman Cancer Center)

  • Maria Spies

    (Department of Biochemistry and Molecular Biology)

  • Kara A. Bernstein

    (UPMC-Hillman Cancer Center
    Department of Biochemistry and Biophysics)

Abstract

Templated DNA repair that occurs during homologous recombination and replication stress relies on RAD51. RAD51 activity is positively regulated by BRCA2 and the RAD51 paralogs. The Shu complex is a RAD51 paralog-containing complex consisting of SWSAP1, SWS1, and SPIDR. We demonstrate that SWSAP1-SWS1 binds RAD51, maintains RAD51 filament stability, and enables strand exchange. Using single-molecule confocal fluorescence microscopy combined with optical tweezers, we show that SWSAP1-SWS1 decorates RAD51 filaments proficient for homologous recombination. We also find SWSAP1-SWS1 enhances RPA diffusion on ssDNA. Importantly, we show human sgSWSAP1 and sgSWS1 knockout cells are sensitive to pharmacological inhibition of PARP and APE1. Lastly, we identify cancer variants in SWSAP1 that alter Shu complex formation. Together, we show that SWSAP1-SWS1 stimulates RAD51-dependent high-fidelity repair and may be an important new cancer therapeutic target.

Suggested Citation

  • Sarah R. Hengel & Katherine G. Oppenheimer & Chelsea M. Smith & Matthew A. Schaich & Hayley L. Rein & Julieta Martino & Kristie E. Darrah & Maggie Witham & Oluchi C. Ezekwenna & Kyle R. Burton & Benne, 2024. "The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51595-0
    DOI: 10.1038/s41467-024-51595-0
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    References listed on IDEAS

    as
    1. Yashpal Rawal & Lijia Jia & Aviv Meir & Shuo Zhou & Hardeep Kaur & Eliza A. Ruben & Youngho Kwon & Kara A. Bernstein & Maria Jasin & Alexander B. Taylor & Sandeep Burma & Robert Hromas & Alexander V. , 2023. "Structural insights into BCDX2 complex function in homologous recombination," Nature, Nature, vol. 619(7970), pages 640-649, July.
    2. Kenichiro Matsuzaki & Shizuka Kondo & Tatsuya Ishikawa & Akira Shinohara, 2019. "Human RAD51 paralogue SWSAP1 fosters RAD51 filament by regulating the anti-recombinase FIGNL1 AAA+ ATPase," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    3. Luke A. Yates & Ricardo J. Aramayo & Nilisha Pokhrel & Colleen C. Caldwell & Joshua A. Kaplan & Rajika L. Perera & Maria Spies & Edwin Antony & Xiaodong Zhang, 2018. "A structural and dynamic model for the assembly of Replication Protein A on single-stranded DNA," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    4. 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.
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