Impeding the single-strand annealing pathway of DNA double-strand break repair by withaferin A-mediated FANCA degradation |
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| Institution: | 1. Department of Biochemistry & Molecular Biology, Miami, FL, 33136, USA;2. Department of Surgery, Miami, FL, 33136, USA;3. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA;1. Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, 250100, PR China;2. Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, PR China;3. Institute of Medical Sciences, The Second Hospital of Shandong University, Jinan, 250033, PR China;3. Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide SA5000, Australia;4. Department of Biochemistry and Microbiology, Ghent University, B-9000 Ghent, Belgium;5. VIB Center for Medical Biotechnology, Ghent, Belgium;6. School of Biological Sciences, University of Adelaide, Adelaide SA5005, Australia;1. Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Essen, Germany;2. Institute of Nuclear Technology and Radiation Protection, National Centre for Scientific Research “Demokritos,’’Aghia Paraskevi Attikis, Athens, Greece;1. David Geffen School of Medicine at University of California Los Angeles, United States;2. Virginia K. Crosson Cancer Center, United States;3. Cancer Specialists of North Florida, United States;4. Comprehensive Cancer Centers of Nevada, United States;5. Central Coast Medical Oncology, United States |
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| Abstract: | FANCA is a key player in the canonical Fanconi anemia (FA) repair pathway. We have recently shown that FANCA also plays an important role in the single-strand annealing sub-pathway (SSA) of DNA double-strand break (DSB) repair by biochemically catalyzing single-strand annealing. Here, we report that a steroidal lactone withaferin A (WA) specifically impedes SSA repair by promoting FANCA downregulation at a sub-micromolar concentration range. We find that WA causes FANCA downregulation post-translationally in a proteasome-dependent manner. This WA-mediated downregulation is achieved through HSP90 inhibition and disruption of the FANCA-HSP90 interaction. WA-mediated FANCA degradation significantly reduces cellular SSA repair, abolishes FANCD2 monoubiquitination, elevates sensitivity to mitomycin C, and results in accumulation of DSBs. Importantly, the WA-induced defect in SSA repair is highly dependent on the absence of FANCA protein and overexpression of exogenous WT-FANCA protein in WA-treated cells significantly complements the repair defect. |
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| Keywords: | Fanconi anemia Double strand break repair Single strand annealing FANCA |
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