title: NF-κB regulates DNA double-strand break repair in conjunction with BRCA1-CtIP complexes.
abstract: NF-κB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosis. Even though NF-κB 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-κB 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-κB 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-κB required the targets ATM and BRCA2. Additionally, we provide evidence that NF-κB 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-κB activation indicating HR stimulation through DSB resection by the interacting CtIP-BRCA1 complex and Rad51 filament formation. Taken together, these results define multiple NF-κB-dependent mechanisms regulating HR induction, and thereby providing a novel intriguing explanation for both NF-κB-mediated resistance to chemo- and radiotherapies as well as for the sensitization by pharmaceutical intervention of NF-κB activation.
authors: Department of Obstetrics and Gynecology, Ulm University, 89075 Ulm, Germany.
authors: Meta
authors: M
authors: Volcic
authors: Sabine
authors: S
authors: Karl
authors: Bernd
authors: B
authors: Baumann
authors: Daniela
authors: D
authors: Salles
authors: Peter
authors: P
authors: Daniel
authors: Simone
authors: S
authors: Fulda
authors: Lisa
authors: L
authors: Wiesmüller
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis; D019313:BRCA1 Protein / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004706:Endodeoxyribonucleases; D059765:Homologous Recombination; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051716:Replication Protein A / Q000032:analysis; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D002352:Carrier Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051716:Replication Protein A; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human