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

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Title: Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells
Authors: Kalchschmidt, JS
Bashford-Rogers, R
Paschos, K
Gillman, AC
Styles, CT
Kellam, P
Allday, MJ
Item Type: Journal Article
Abstract: 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.
Issue Date: 23-May-2016
Date of Acceptance: 12-Apr-2016
URI: http://hdl.handle.net/10044/1/33226
DOI: http://dx.doi.org/10.1084/jem.20160120
ISSN: 1540-9538
Publisher: Rockefeller University Press
Start Page: 921
End Page: 928
Journal / Book Title: Journal of Experimental Medicine
Volume: 213
Issue: 6
Copyright Statement: © 2016 Kalchschmidt et al.
Sponsor/Funder: Wellcome Trust
Wellcome Trust
Wellcome Trust
Funder's Grant Number: 085988/Z/08/Z
097005/Z/11/Z
099273/Z/12/Z
Keywords: Immunology
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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