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Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and
somatic mutations in B cells
#MMPMID27217538
Kalchschmidt JS
; Bashford-Rogers R
; Paschos K
; Gillman AC
; Styles CT
; Kellam P
; Allday MJ
J Exp Med
2016[May]; 213
(6
): 921-8
PMID27217538
show ga
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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