Journal
EXPERIMENTAL CELL RESEARCH
Volume 322, Issue 1, Pages 178-192Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2014.01.004
Keywords
Activation-induced cytidine deaminase; CTNNBL1; Subnuclear trafficking; Cajal bodies; Nuclear speckles; Transcription-coupled splicing
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Funding
- Liaison Committee between the Central Norway Regional Health Authority (RHA)
- Norwegian University of Science and Technology (NTNU)
- Research Council of Norway (National Program for Research in Functional Genomics in Norway (FUGE))
- Norwegian Cancer Association
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Activation-induced cytidine deaminase (AID) is the mutator enzyme in adaptive immunity. AID initiates the antibody diversification processes in activated B cells by deaminating cytosine to uracil in immunoglobulin genes. To some extent other genes are also targeted, which may lead to genome instability and B cell malignancy. Thus, it is crucial to understand its targeting and regulation mechanisms. AID is regulated at several levels including subcellular compartmentalization. However, the complex nuclear distribution and trafficking of AID has not been studied in detail previously. In this work, we examined the subnuclear localization of AID and its interaction partner CTNNBL1 and found that they associate with spliceosome-associated structures including Cajal bodies and nuclear speckles. Moreover, protein kinase A (PI(A), which activates AID by phosphorylation at Ser38, is present together with AID in nuclear speckles. Importantly, we demonstrate that AID physically associates with the major spliceosome subunits (small nuclear ribonucleoproteins, snRNPs), as well as other essential splicing components, in addition to the transcription machinery. Based on our findings and the literature, we suggest a transcription-coupled splicing-associated model for AID targeting and activation. (c) 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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