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

Sarah R Hengel; Katherine Oppenheimer; Chelsea Smith; Matthew A Schaich; Hayley L Rein; Julieta Martino; Kristie Darrah; Oluchi Ezekwenna; Kyle Burton; Bennett Van Houten; Maria Spies; Kara A Bernstein

doi:10.1101/2024.02.14.580393

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

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

Sarah R Hengel, Katherine Oppenheimer, Chelsea Smith, Matthew A Schaich, Hayley L Rein, Julieta Martino, Kristie Darrah, Oluchi Ezekwenna, Kyle Burton, Bennett Van Houten, …

bioRxiv : the preprint server for biology

Cold Spring Harbor Laboratory

02/15/2024

DOI: 10.1101/2024.02.14.580393

PMCID: PMC10888808

PMID: 38405734

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https://doi.org/10.1101/2024.02.14.580393View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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 and SWS1. 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 and knockout cells are sensitive to pharmacological inhibition of PARP and APE1. Lastly, we identify cancer variants in SWSAP1 that alter SWS1 complex formation. Together, we show that SWSAP1-SWS1 stimulates RAD51-dependent high-fidelity repair and may be an important new cancer therapeutic target.

Details

Title: Subtitle: The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA
Creators: Sarah R Hengel - University of Pennsylvania
Katherine Oppenheimer - University of Pittsburgh
Chelsea Smith - University of North Carolina at Chapel Hill
Matthew A Schaich - University of Pittsburgh
Hayley L Rein - University of Pittsburgh
Julieta Martino - University of Pittsburgh
Kristie Darrah - University of Pennsylvania
Oluchi Ezekwenna - Tufts University
Kyle Burton - Tufts University
Bennett Van Houten - University of Pittsburgh
Maria Spies - University of Iowa
Kara A Bernstein - University of Pittsburgh
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2024.02.14.580393
PMID: 38405734
PMCID: PMC10888808
Publisher: Cold Spring Harbor Laboratory; United States
Language: English
Date posted: 02/15/2024
Academic Unit: Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984563560202771

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