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Proteasomal degradation restricts the nuclear lifespan of AID

Activation-induced cytidine deaminase (AID) initiates all postrearrangement processes that diversify the immunoglobulin repertoire by specific deamination of cytidines at the immunoglobulin (Ig) locus. As uncontrolled expression of AID is potentially mutagenic, different types of regulation, particu...

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Autores principales: Aoufouchi, Said, Faili, Ahmad, Zober, Carole, D'Orlando, Orietta, Weller, Sandra, Weill, Jean-Claude, Reynaud, Claude-Agnès
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413033/
https://www.ncbi.nlm.nih.gov/pubmed/18474627
http://dx.doi.org/10.1084/jem.20070950
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author Aoufouchi, Said
Faili, Ahmad
Zober, Carole
D'Orlando, Orietta
Weller, Sandra
Weill, Jean-Claude
Reynaud, Claude-Agnès
author_facet Aoufouchi, Said
Faili, Ahmad
Zober, Carole
D'Orlando, Orietta
Weller, Sandra
Weill, Jean-Claude
Reynaud, Claude-Agnès
author_sort Aoufouchi, Said
collection PubMed
description Activation-induced cytidine deaminase (AID) initiates all postrearrangement processes that diversify the immunoglobulin repertoire by specific deamination of cytidines at the immunoglobulin (Ig) locus. As uncontrolled expression of AID is potentially mutagenic, different types of regulation, particularly nucleocytoplasmic shuttling, restrict the likelihood of AID–deoxyribonucleic acid encounters. We studied additional mechanisms of regulation affecting the stability of the AID protein. No modulation of protein accumulation according to the cell cycle was observed in a Burkitt's lymphoma cell line. In contrast, the half-life of AID was markedly reduced in the nucleus, and this destabilization was accompanied by a polyubiquitination that was revealed in the presence of proteasome inhibitors. The same compartment-specific degradation was observed in activated mouse B cells, and also in a non–B cell line. No specific lysine residues could be linked to this degradation, so it remains unclear whether polyubiquitination proceeds through several alternatives sites or through the protein N terminus. The nuclear-restricted form of AID displayed enhanced mutagenicity at both Ig and non-Ig loci, most notably at TP53, suggesting that modulation of nuclear AID content through proteasomal degradation may represent another level of control of AID activity.
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spelling pubmed-24130332008-12-09 Proteasomal degradation restricts the nuclear lifespan of AID Aoufouchi, Said Faili, Ahmad Zober, Carole D'Orlando, Orietta Weller, Sandra Weill, Jean-Claude Reynaud, Claude-Agnès J Exp Med Articles Activation-induced cytidine deaminase (AID) initiates all postrearrangement processes that diversify the immunoglobulin repertoire by specific deamination of cytidines at the immunoglobulin (Ig) locus. As uncontrolled expression of AID is potentially mutagenic, different types of regulation, particularly nucleocytoplasmic shuttling, restrict the likelihood of AID–deoxyribonucleic acid encounters. We studied additional mechanisms of regulation affecting the stability of the AID protein. No modulation of protein accumulation according to the cell cycle was observed in a Burkitt's lymphoma cell line. In contrast, the half-life of AID was markedly reduced in the nucleus, and this destabilization was accompanied by a polyubiquitination that was revealed in the presence of proteasome inhibitors. The same compartment-specific degradation was observed in activated mouse B cells, and also in a non–B cell line. No specific lysine residues could be linked to this degradation, so it remains unclear whether polyubiquitination proceeds through several alternatives sites or through the protein N terminus. The nuclear-restricted form of AID displayed enhanced mutagenicity at both Ig and non-Ig loci, most notably at TP53, suggesting that modulation of nuclear AID content through proteasomal degradation may represent another level of control of AID activity. The Rockefeller University Press 2008-06-09 /pmc/articles/PMC2413033/ /pubmed/18474627 http://dx.doi.org/10.1084/jem.20070950 Text en © 2008 Aoufouchi et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Articles
Aoufouchi, Said
Faili, Ahmad
Zober, Carole
D'Orlando, Orietta
Weller, Sandra
Weill, Jean-Claude
Reynaud, Claude-Agnès
Proteasomal degradation restricts the nuclear lifespan of AID
title Proteasomal degradation restricts the nuclear lifespan of AID
title_full Proteasomal degradation restricts the nuclear lifespan of AID
title_fullStr Proteasomal degradation restricts the nuclear lifespan of AID
title_full_unstemmed Proteasomal degradation restricts the nuclear lifespan of AID
title_short Proteasomal degradation restricts the nuclear lifespan of AID
title_sort proteasomal degradation restricts the nuclear lifespan of aid
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413033/
https://www.ncbi.nlm.nih.gov/pubmed/18474627
http://dx.doi.org/10.1084/jem.20070950
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