The NF-kappaB canonical pathway is involved in the control of the exonucleolytic processing of coding ends during V(D)J recombination

The Journal of Immunology : Official Journal of the American Association of Immunologists
M Margarida Souto-CarneiroPeter E Lipsky

Abstract

V(D)J recombination is essential to produce an Ig repertoire with a large range of Ag specificities. Although NF-kappaB-binding sites are present in the human and mouse IgH, Igkappa, and Iglambda enhancer modules and RAG expression is controlled by NF-kappaB, it is not known whether NF-kappaB regulates V(D)J recombination mechanisms after RAG-mediated dsDNA breaks. To clarify the involvement of NF-kappaB in human V(D)J recombination, we amplified Ig gene rearrangements from individual peripheral B cells of patients with X-linked anhidrotic ectodermal dysplasia with hyper-IgM syndrome (HED-ID) who have deficient expression of the NF-kappaB essential modulator (NEMO/Ikkgamma). The amplification of nonproductive Ig gene rearrangements from HED-ID B cells reflects the influence of the Ikkgamma-mediated canonical NF-kappaB pathway on specific molecular mechanisms involved in V(D)J recombination. We found that the CDR3(H) from HED-ID B cells were abnormally long, as a result of a marked reduction in the exonuclease activity on the V, D, and J germline coding ends, whereas random N-nucleotide addition and palindromic overhangs (P nucleotides) were comparable to controls. This suggests that an intact canonical NF-kappaB pathway is esse...Continue Reading

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Citations

Aug 1, 2018·International Journal of Molecular Sciences·Christine E HellwegChrista Baumstark-Khan
Sep 13, 2011·Nucleic Acids Research·Meta VolcicLisa Wiesmüller
Apr 26, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Nancy S LongoPeter E Lipsky
Sep 23, 2020·Signal Transduction and Targeted Therapy·Hui YuHongbo Hu
Apr 22, 2008·Immunology and Allergy Clinics of North America·Jacinta BustamanteJean-Laurent Casanova

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