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

作者：Volcic Meta; Karl Sabine; Baumann Bernd; Salles Daniela; Daniel Peter; Fulda Simone; Wiesmueller Lisa

来源：Nucleic Acids Research, 2012, 40(1): 181-195.

DOI：10.1093/nar/gkr687

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 crosstalk 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.

• 出版日期2012-1