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Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells

Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma. Using various Epstein-Ba...

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Autores principales: Kalchschmidt, Jens S., Bashford-Rogers, Rachael, Paschos, Kostas, Gillman, Adam C.T., Styles, Christine T., Kellam, Paul, Allday, Martin J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886369/
https://www.ncbi.nlm.nih.gov/pubmed/27217538
http://dx.doi.org/10.1084/jem.20160120
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author Kalchschmidt, Jens S.
Bashford-Rogers, Rachael
Paschos, Kostas
Gillman, Adam C.T.
Styles, Christine T.
Kellam, Paul
Allday, Martin J.
author_facet Kalchschmidt, Jens S.
Bashford-Rogers, Rachael
Paschos, Kostas
Gillman, Adam C.T.
Styles, Christine T.
Kellam, Paul
Allday, Martin J.
author_sort Kalchschmidt, Jens S.
collection PubMed
description Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma. Using various Epstein-Barr virus (EBV) recombinants, we provide definitive evidence that the viral nuclear protein EBNA3C is essential in EBV-infected primary B cells for the induction of AID mRNA and protein. Using lymphoblastoid cell lines (LCLs) established with EBV recombinants conditional for EBNA3C function, this was confirmed, and it was shown that transactivation of the AID gene (AICDA) is associated with EBNA3C binding to highly conserved regulatory elements located proximal to and upstream of the AICDA transcription start site. EBNA3C binding initiated epigenetic changes to chromatin at specific sites across the AICDA locus. Deep sequencing of cDNA corresponding to the IgH V-D-J region from the conditional LCL was used to formally show that SHM is activated by functional EBNA3C and induction of AID. These data, showing the direct targeting and induction of functional AID by EBNA3C, suggest a novel role for EBV in the etiology of B cell cancers, including endemic Burkitt lymphoma.
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spelling pubmed-48863692016-11-30 Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells Kalchschmidt, Jens S. Bashford-Rogers, Rachael Paschos, Kostas Gillman, Adam C.T. Styles, Christine T. Kellam, Paul Allday, Martin J. J Exp Med Research Articles Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma. Using various Epstein-Barr virus (EBV) recombinants, we provide definitive evidence that the viral nuclear protein EBNA3C is essential in EBV-infected primary B cells for the induction of AID mRNA and protein. Using lymphoblastoid cell lines (LCLs) established with EBV recombinants conditional for EBNA3C function, this was confirmed, and it was shown that transactivation of the AID gene (AICDA) is associated with EBNA3C binding to highly conserved regulatory elements located proximal to and upstream of the AICDA transcription start site. EBNA3C binding initiated epigenetic changes to chromatin at specific sites across the AICDA locus. Deep sequencing of cDNA corresponding to the IgH V-D-J region from the conditional LCL was used to formally show that SHM is activated by functional EBNA3C and induction of AID. These data, showing the direct targeting and induction of functional AID by EBNA3C, suggest a novel role for EBV in the etiology of B cell cancers, including endemic Burkitt lymphoma. The Rockefeller University Press 2016-05-30 /pmc/articles/PMC4886369/ /pubmed/27217538 http://dx.doi.org/10.1084/jem.20160120 Text en © 2016 Kalchschmidt 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.rupress.org/terms). 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 Research Articles
Kalchschmidt, Jens S.
Bashford-Rogers, Rachael
Paschos, Kostas
Gillman, Adam C.T.
Styles, Christine T.
Kellam, Paul
Allday, Martin J.
Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells
title Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells
title_full Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells
title_fullStr Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells
title_full_unstemmed Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells
title_short Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells
title_sort epstein-barr virus nuclear protein ebna3c directly induces expression of aid and somatic mutations in b cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886369/
https://www.ncbi.nlm.nih.gov/pubmed/27217538
http://dx.doi.org/10.1084/jem.20160120
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