Journal article
Redox regulation of RAD51 Cys319 and homologous recombination by peroxiredoxin 1
Redox biology, Vol.56, p.102443
10/2022
DOI: 10.1016/j.redox.2022.102443
PMCID: PMC9450138
PMID: 36058112
Abstract
RAD51 is a critical recombinase that functions in concert with auxiliary mediator proteins to direct the homologous recombination (HR) DNA repair pathway. We show that Cys319 RAD51 possesses nucleophilic characteristics and is important for irradiation-induced RAD51 foci formation and resistance to inhibitors of poly (ADP-ribose) polymerase (PARP). We have previously identified that cysteine (Cys) oxidation of proteins can be important for activity and modulated via binding to peroxiredoxin 1 (PRDX1). PRDX1 reduces peroxides and coordinates the signaling actions of protein binding partners. Loss of PRDX1 inhibits irradiation-induced RAD51 foci formation and represses HR DNA repair. PRDX1-deficient human breast cancer cells and mouse embryonic fibroblasts display disrupted RAD51 foci formation and decreased HR, resulting in increased DNA damage and sensitization of cells to irradiation. Following irradiation cells deficient in PRDX1 had increased incorporation of the sulfenylation probe DAz-2 in RAD51 Cys319, a functionally-significant, thiol that PRDX1 is critical for maintaining in a reduced state. Molecular dynamics (MD) simulations of dT-DNA bound to a non-oxidized RAD51 protein showed tight binding throughout the simulation, while dT-DNA dissociated from an oxidized Cys319 RAD51 filament. These novel data establish RAD51 Cys319 as a functionally-significant site for the redox regulation of HR and cellular responses to IR.
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•A functionally-significant Cys319 was identified in RAD51 that possesses nucleophilic characteristics.•RAD51 Cys319 plays a central role in RAD51-mediated repair of DNA double strand breaks (DSB).•Loss of peroxiredoxin 1 (PRDX1) impairs DNA DSB repair by homologous recombination and results in DNA damage.•PRDX1 is critical for maintaining RAD51 Cys319 in a reduced state.•Molecular dynamic (MD) simulations suggest ssDNA to dissociate from sulfenylated and not reduced RAD51 Cys319.
Details
- Title: Subtitle
- Redox regulation of RAD51 Cys319 and homologous recombination by peroxiredoxin 1
- Creators
- John J. Skoko - University of PittsburghJuxiang Cao - Medical University of South CarolinaDavid Gaboriau - Ollscoil na Gaillimhe – University of GalwayMyriam Attar - University of PittsburghAlparslan Asan - University of PittsburghLisa Hong - University of PittsburghCandice E. Paulsen - Scripps Research InstituteHongqiang Ma - University of PittsburghYang Liu - University of PittsburghHanzhi Wu - Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USACristina M. Furdui - Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USAYefim Manevich - Medical University of South CarolinaCiaran G. Morrison - Ollscoil na Gaillimhe – University of GalwayErika T. Brown - Dartmouth Geisel School of Medicine, Hanover, NH, 03755, USADaniel Normolle - University of PittsburghMaria Spies - University of IowaMichael Ashley Spies - University of IowaKate Carroll - Scripps Research InstituteCarola A. Neumann - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.56, p.102443
- DOI
- 10.1016/j.redox.2022.102443
- PMID
- 36058112
- PMCID
- PMC9450138
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- Elsevier B.V
- Language
- English
- Date published
- 10/2022
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Biochemistry and Molecular Biology; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984293556802771
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