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NF-κB regulates DNA double-strand break repair in conjunction with BRCA1-CtIP complexes

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Item Type:Article
Title:NF-κB regulates DNA double-strand break repair in conjunction with BRCA1-CtIP complexes
Creators Name:Volcic, M. and Karl, S. and Baumann, B. and Salles, D. and Daniel, P. and Fulda, S. and Wiesmueller, L.
Abstract:NF-{kappa}B is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosis. Even though NF-{kappa}B can be activated by DNA damage via Ataxia telangiectasia-mutated (ATM) signalling, little was known about an involvement in DNA repair. In this work, we dissected distinct DNA double-strand break (DSB) repair mechanisms revealing a stimulatory role of NF-{kappa}B in homologous recombination (HR). This effect was independent of chromatin context, cell cycle distribution or cross-talk with p53. It was not mediated by the transcriptional NF-{kappa}B targets Bcl2, BAX or Ku70, known for their dual roles in apoptosis and DSB repair. A contribution by Bcl-xL was abrogated when caspases were inhibited. Notably, HR induction by NF-{kappa}B required the targets ATM and BRCA2. Additionally, we provide evidence that NF-{kappa}B interacts with CtIP-BRCA1 complexes and promotes BRCA1 stabilization, and thereby contributes to HR induction. Immunofluorescence analysis revealed accelerated formation of replication protein A (RPA) and Rad51 foci upon NF-{kappa}B activation indicating HR stimulation through DSB resection by the interacting CtIP-BRCA1 complex and Rad51 filament formation. Taken together, these results define multiple NF-{kappa}B-dependent mechanisms regulating HR induction, and thereby providing a novel intriguing explanation for both NF-{kappa}B-mediated resistance to chemo- and radiotherapies as well as for the sensitization by pharmaceutical intervention of NF-{kappa}B activation.
Keywords:Antineoplastic Agents, Apoptosis, BRCA1 Protein, Carrier Proteins, DNA Damage, DNA Repair, Double-Stranded DNA Breaks, Homologous Recombination, NF-kappa B, Nuclear Proteins, Proto-Oncogene Proteins c-bcl-2, Replication Protein A, Transcription Factor RelA, Tumor Cell Line, Tumor Necrosis Factor-alpha
Source:Nucleic Acids Research
ISSN:0305-1048
Publisher:Oxford University Press (U.K.)
Volume:40
Number:1
Page Range:181-195
Date:January 2012
Official Publication:https://doi.org/10.1093/nar/gkr687
PubMed:View item in PubMed

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