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

Nucleic Acids Res. 2012 Jan;40(1):181-95. doi: 10.1093/nar/gkr687. Epub 2011 Sep 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / toxicity
  • Apoptosis
  • BRCA1 Protein / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded*
  • DNA Damage
  • DNA Repair*
  • Endodeoxyribonucleases
  • Homologous Recombination
  • Humans
  • NF-kappa B / metabolism*
  • Nuclear Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Replication Protein A / analysis
  • Transcription Factor RelA / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology


  • Antineoplastic Agents
  • BRCA1 Protein
  • Carrier Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Replication Protein A
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Endodeoxyribonucleases
  • RBBP8 protein, human