NF-κB regulates DNA double-strand break repair in conjunction with BRCA1-CtIP complexes
- 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
Author: | Meta Volcic, Sabine Karl, Bernd Baumann, Daniela Salles, Peter Daniel, Simone FuldaORCiDGND, Lisa Wiesmüller |
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URN: | urn:nbn:de:hebis:30:3-248407 |
URL: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245919/ |
DOI: | https://doi.org/10.1093/nar/gkr687 |
ISSN: | 1362-4962 |
ISSN: | 0305-1048 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/21908405 |
Parent Title (English): | Nucleic acids research |
Publisher: | Oxford Univ. Press |
Place of publication: | Oxford |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2011/09/09 |
Date of first Publication: | 2011/09/09 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2012/05/23 |
Volume: | 40 |
Issue: | 1 |
Page Number: | 15 |
First Page: | 181 |
Last Page: | 195 |
Note: | (c) The Author(s) 2011. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
HeBIS-PPN: | 357329082 |
Institutes: | Medizin / Medizin |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Sammlungen: | Universitätspublikationen |
Sammlung Biologie / Sondersammelgebiets-Volltexte | |
Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell 3.0 |