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

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, Bennett Houten, Maria Spies and Kara A. Bernstein ()
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Sarah R. Hengel: UPMC-Hillman Cancer Center
Katherine G. Oppenheimer: UPMC-Hillman Cancer Center
Chelsea M. Smith: UPMC-Hillman Cancer Center
Matthew A. Schaich: UPMC-Hillman Cancer Center
Hayley L. Rein: UPMC-Hillman Cancer Center
Julieta Martino: UPMC-Hillman Cancer Center
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

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51595-0

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