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

Autor: Hengel SR; University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, UPMC-Hillman Cancer Center, Pittsburgh, PA, USA. sarah.hengel@tufts.edu.; Tufts University, Department of Biology, Medford, MA, USA. sarah.hengel@tufts.edu., Oppenheimer KG; University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, UPMC-Hillman Cancer Center, Pittsburgh, PA, USA., Smith CM; University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, UPMC-Hillman Cancer Center, Pittsburgh, PA, USA.; University of North Carolina at Chapel Hill, Department of Pathology and Laboratory Medicine, Chapel Hill, NC, USA., Schaich MA; University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, UPMC-Hillman Cancer Center, Pittsburgh, PA, USA., Rein HL; University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, UPMC-Hillman Cancer Center, Pittsburgh, PA, USA., Martino J; University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, UPMC-Hillman Cancer Center, Pittsburgh, PA, USA.; GeneDx, Gaithersburg, MD, USA., Darrah KE; University of Pennsylvania School of Medicine, Penn Center for Genome Integrity, Department of Biochemistry and Biophysics, 421 Curie Boulevard, Philadelphia, PA, USA., Witham M; Tufts University, Department of Biology, Medford, MA, USA., Ezekwenna OC; Tufts University, Department of Biology, Medford, MA, USA., Burton KR; Tufts University, Department of Biology, Medford, MA, USA., Van Houten B; University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, UPMC-Hillman Cancer Center, Pittsburgh, PA, USA., Spies M; University of Iowa, Department of Biochemistry and Molecular Biology, Iowa City, IA, USA., Bernstein KA; University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, UPMC-Hillman Cancer Center, Pittsburgh, PA, USA. kara.bernstein@pennmedicine.upenn.edu.; University of Pennsylvania School of Medicine, Penn Center for Genome Integrity, Department of Biochemistry and Biophysics, 421 Curie Boulevard, Philadelphia, PA, USA. kara.bernstein@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 21; Vol. 15 (1), pp. 7197. Date of Electronic Publication: 2024 Aug 21.
DOI: 10.1038/s41467-024-51595-0
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: