The NF-κB Canonical Pathway Is Involved in the Control of the Exonucleolytic Processing of Coding Ends during V(D)J Recombination

Souto-Carneiro, Margarida; Fritsch, R; Sepúlveda, Nuno; Lagareiro, M. João; Morgado, Nuno; Longo, Nancy S.; Lipsky, Peter E.

doi:10.4049/jimmunol.180.2.1040

Cited by 11 publications

(7 citation statements)

References 68 publications

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“…Recruitment of CtIP by BRCA1 is necessary for HR but not error-prone NHEJ shifting the balance of DSB repair to HR (26). Notably, Souto-Carneiro et al (40) found that NF-κB is involved in controlling the exonucleolytic activity on the coding ends during V(D)J recombination, whereby the authors excluded an influence of NF-κB on terminal deoxynucleotide transferase, Artemis and DNA-PKcs.…”

Section: Discussionmentioning

confidence: 99%

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

Volcic

Karl

Baumann

et al. 2011

Nucleic Acids Research

121

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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.

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Section: Discussionmentioning

confidence: 99%

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

Volcic

Karl

Baumann

et al. 2011

Nucleic Acids Research

121

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“…To gain further insight into the mechanisms that shape the xenomouse repertoire, CDRH3 and D-JH pairing in the nonproductive repertoire were analyzed. Developing human B cells may undergo repetitive rounds of D to JH recombination between the common lymphoid precursor and the pre-B cell stage before a final DJH recombination occurs (38). This process is evident in the significantly increased use of distal D genes with JH5 and JH6 segments in the healthy donor B cells (p = 0.003) (Fig.…”

Section: Xenomouse Rearrangements Have a Locus Positional Bias In D-jmentioning

confidence: 99%

Mechanisms That Shape Human Antibody Repertoire Development in Mice Transgenic for Human Ig H and L Chain Loci

Longo

Rogosch

Zemlin

et al. 2017

The Journal of Immunology

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To determine the impact of the milieu on the development of the human B cell repertoire, we carried out a comprehensive analysis of productive and nonproductive Ig gene rearrangements from transgenic mice engineered to express single copies of the unrearranged human H chain and L chain Ig gene loci. By examining the nonproductive repertoire as an indication of the immediate product of the rearrangement machinery without an impact of selection, we discovered that the distribution of human rearrangements arising in the mouse was generally comparable to that seen in humans. However, differences between the distribution of nonproductive and productive rearrangements that reflect the impact of selection suggested species-specific selection played a role in shaping the respective repertoires. Although expression of some VH genes was similar in mouse and human (IGHV3-23, IGHV3-30, and IGHV4-59), other genes behaved differently (IGHV3-33, IGHV3-48, IGHV4-31, IGHV4-34, and IGHV1-18). Gene selection differences were also noted in L chains. Notably, nonproductive human VH rearrangements in the transgenic mice expressed shorter CDRH3 with less N addition. Even the CDRH3s in the productive rearrangements were shorter in length than those of the normal human productive repertoire. Amino acids in the CDRH3s in both species showed positive selection of tyrosines and glycines, and negative selection of leucines. The data indicate that the environment in which B cells develop can affect the expressed Ig repertoire by exerting influences on the distribution of expressed VH and VL genes and by influencing the amino acid composition of the Ag binding site.

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“…Thus, whereas in WT cells the frequency of P-additions is similar at DJ H and V H D, in Fanca −/− cells we found 3 times more P-additions at DJ H than at V H D junctions. An elevated frequency of sequences with P-additions, but at both DJ H and V H D junctions, was previously reported in X- linked anhidrotic ectodermal dysplasia with hyper-IgM syndrome (HED-ID), a rare pathology due to a genetic determined deficiency in NF-kB activation29. In HED-ID exacerbated P-nucleotide additions have been directly associated to an altered exonucleolytic processing of the coding ends.…”

Section: Discussionmentioning

confidence: 73%

V(D)J recombination process and the Pre-B to immature B-cells transition are altered in Fanca−/− mice

Nguyen¹,

Pawlikowska²,

Firlej³

et al. 2016

Sci Rep

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B-lymphocytes in the bone marrow (BM) must generate a functional B-cell receptor and overcome the negative selection induced by reactivity with autoantigens. Two rounds of DNA recombination are required for the production of functional immunoglobulin heavy (Ig-HCs) and light (LCs) chains necessary for the continuation of B-lymphocyte development in the BM. Both rounds depend on the joint action of recombination activating gene-1 (RAG-1) and RAG-2 endonucleases with the DNA non-homologous end-joining pathway. Loss of the FANC gene leads to the chromosome breakage and cancer predisposition syndrome Fanconi anemia. Because the FANC proteins are involved in certain aspects of the recombination process, we sought to determine the impact of the FANC pathway on the Ig diversification process using Fanca−/− mice. In this work we demonstrated that Fanca−/− animals have a mild B-cell differentiation defect characterized by a specific alteration of the IgM− to IgM+ transition of the B220low B-cell population. Pre-B cells from Fanca−/− mice show evidence of impaired kLC rearrangement at the level of the Vk-Jk junction. Furthermore, Fanca−/− mice showed a skewed Vκ gene usage during formation of the LCs Vk-Jk junctions. Therefore, the Fanca protein appears as a yet unidentified factor involved in the primary diversification of Ig.

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The NF-κB Canonical Pathway Is Involved in the Control of the Exonucleolytic Processing of Coding Ends during V(D)J Recombination

Cited by 11 publications

References 68 publications

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

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

Mechanisms That Shape Human Antibody Repertoire Development in Mice Transgenic for Human Ig H and L Chain Loci

V(D)J recombination process and the Pre-B to immature B-cells transition are altered in Fanca−/− mice

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