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

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.

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Publication Details

Journal
Nature Communications
Published
2024-08-21
DOI
https://doi.org/10.1038/s41467-024-51595-0
Citations
8
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
1.87

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article

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

Kristie E. Darrah, Chelsea M. Smith, Sarah R Hengel, Maria Spies et al.
8 citations
Nature Communications
DNA Repair Mechanisms
1.87
article

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

Kristie E. Darrah, Chelsea M. Smith, Sarah R Hengel, Maria Spies, Bennett Van Houten, Katherine G. Oppenheimer, Hayley L. Rein, Kara Anne Bernstein, Matthew A. Schaich, Oluchi C. Ezekwenna, Maggie Witham, K. Burton
article en
8 citations

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.

Nature CommunicationsVol. 15(1)
University of North Carolina at Chapel Hill (US), Tufts University (US), University of Iowa (US), Penn Center for AIDS Research (US), UPMC Hillman Cancer Center (US), University of Pennsylvania (US)
University of Pennsylvania, University of Pittsburgh, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences
Good health and well-being
Openalex Percentile: Top 14%
DNA Repair Mechanisms
1.87
DOIOpen Access PDFOpenAlex
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