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Amino-terminal phosphorylation of activation-induced cytidine deaminase suppresses c-myc/IgH translocation

Item Type:Article
Title:Amino-terminal phosphorylation of activation-induced cytidine deaminase suppresses c-myc/IgH translocation
Creators Name:Gazumyan, A., Timachova, K., Yuen, G., Siden, E., Di Virgilio, M., Woo, E.M., Chait, B.T., Reina San-Martin, B., Nussenzweig, M.C. and McBride, K.M.
Abstract:Activation-induced cytidine deaminase (AID) is a mutator enzyme that initiates class switch recombination and somatic hypermutation of immunoglobulin genes (Ig) in B lymphocytes. However, AID also produces off-target DNA damage, including mutations in oncogenes and double-stranded breaks that can serve as substrates for oncogenic chromosomal translocations. AID is strictly regulated by a number of mechanisms, including phosphorylation at serine 38 and threonine 140, which increase activity. Here we show that phosphorylation can also suppress AID activity in vivo. Serine 3 is a novel phospho-acceptor which, when mutated to alanine, leads to increased class switching and c-myc/IgH translocations without affecting AID levels or catalytic activity. Conversely, increasing AID phosphorylation specifically on serine 3 by interfering with serine/threonine protein phosphatase 2A (PP2A) leads to decreased class switching. We conclude that AID activity and its oncogenic potential can be downregulated by phosphorylation of serine 3 and that this process is controlled by PP2A.
Keywords:Amino Acid Sequence, Amino Acid Substitution, Cytidine Deaminase, Enzyme Inhibitors, Fibroblasts, Genetic Recombination, Genetic Translocation, Immunoglobulin Class Switching, Immunoglobulin Heavy Chains, Immunoglobulin Somatic Hypermutation, Molecular Sequence Data, Mutant Proteins, Phosphorylation, Phosphoserine, Protein Phosphatase 2, Proto-Oncogene Proteins c-myc, Animals, Mice
Source:Molecular and Cellular Biology
Publisher:American Society for Microbiology
Page Range:442-429
Date:February 2011
Official Publication:https://doi.org/10.1128/MCB.00349-10
PubMed:View item in PubMed

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