Document Detail


GANP-mediated recruitment of activation-induced cytidine deaminase to cell nuclei and to immunoglobulin variable region DNA.
MedLine Citation:
PMID:  20507984     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AID (activation-induced cytidine deaminase) catalyzes transcription-dependent deamination of C --> U in immunoglobulin variable (IgV) regions to initiate somatic hypermutation (SHM) in germinal center B-cells. SHM is essential in generating high affinity antibodies. Here we show that when coexpressed with GANP (germinal center-associated nuclear protein) in COS-7 cells, AID is transported from the cytoplasm and concentrated in the nucleus. GANP forms a complex with AID in cotransfected cells in vivo and in vitro. We have isolated AID mutants that bind with reduced affinity to GANP compared with wild type AID. One of these mutants, AID (D143A) binds GANP with a 10-fold lower affinity compared with wild type AID yet retains substantial C-deamination activity in vitro. Mutant AID (D143A) remains localized predominantly in the cytoplasm when coexpressed with GANP. Exogenous expression of GANP in Ramos B-cells promotes binding of AID to IgV DNA and mRNA and increases SHM frequency. These data suggest that GANP may serve as an essential link required to transport AID to B-cell nuclei and to target AID to actively transcribed IgV regions.
Authors:
Kazuhiko Maeda; Shailendra Kumar Singh; Kazufumi Eda; Masahiro Kitabatake; Phuong Pham; Myron F Goodman; Nobuo Sakaguchi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-05-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-26     Completed Date:  2010-09-14     Revised Date:  2013-01-07    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23945-53     Citation Subset:  IM    
Affiliation:
Department of Immunology, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
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MeSH Terms
Descriptor/Qualifier:
Acetyltransferases / genetics*,  metabolism
Animals
COS Cells
Cell Nucleus / metabolism*
Cercopithecus aethiops
Cytidine Deaminase / chemistry,  genetics*
Cytoplasm / metabolism
Humans
Immunoglobulin Variable Region / genetics*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Nuclear Proteins / genetics*,  metabolism
Phosphoproteins / genetics*,  metabolism
Protein Interaction Mapping
Grant Support
ID/Acronym/Agency:
ES013192/ES/NIEHS NIH HHS; GM21422/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/GANP protein, mouse; 0/Immunoglobulin Variable Region; 0/Nuclear Proteins; 0/Phosphoproteins; EC 2.3.1.-/Acetyltransferases; EC 2.3.1.-/MCM3AP protein, human; EC 3.5.4.-/AICDA (activation-induced cytidine deaminase); EC 3.5.4.5/Cytidine Deaminase
Comments/Corrections

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