De novo Protein Synthesis Is Required for Activation-Induced Cytidine Deaminase-Dependent DNA Cleavage in Immunoglobulin Class Switch Recombination

Activation-induced cytidine deaminase is required for the DNA cleavage step of Ig class switch recombination (CSR). However, its molecular mechanism is controversial. RNA-editing hypothesis postulates that activation-induced cytidine deaminase deaminates cytosine in an unknown mRNA to generate a new...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-08, Vol.101 (35), p.13003-13007
Main Authors: Begum, Nasim A., Kinoshita, Kazuo, Muramatsu, Masamichi, Nagaoka, Hitoshi, Shinkura, Reiko, Honjo, Tasuku
Format: Article
Language:English
Subjects:
AIDS
Animals
B lymphocytes
Biological Sciences
Cell lines
Cytidine Deaminase - genetics
Cytidine Deaminase - metabolism
Deoxyribonucleic acid
DNA
DNA cleavage
Genetic loci
Histones - metabolism
Immunoglobulin Class Switching - genetics
Immunoglobulin Class Switching - physiology
Immunoglobulin Heavy Chains - genetics
Immunoglobulin Heavy Chains - physiology
Immunology
Messenger RNA
Mice
Mice, Knockout
Polymerase chain reaction
Protein synthesis
Proteins
Ribonucleic acid
RNA
RNA Editing
Spleen - metabolism
Spleen cells
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Summary:Activation-induced cytidine deaminase is required for the DNA cleavage step of Ig class switch recombination (CSR). However, its molecular mechanism is controversial. RNA-editing hypothesis postulates that activation-induced cytidine deaminase deaminates cytosine in an unknown mRNA to generate a new mRNA encoding an endonuclease for CSR and thus predicts that DNA cleavage depends on de novo protein synthesis. On the other hand, DNA deamination hypothesis proposes that DNA cleavage is initiated by cytosine deamination in DNA, followed by uracil removal by uracil DNA glycosylase. By using the chromatin immunoprecipitation assay to detect γ-H2AX focus formation as a marker for DNA cleavage, we found that cycloheximide inhibited DNA cleavage in the Ig heavy-chain locus during CSR. Requirement of protein synthesis in the DNA cleavage step of CSR strengthens the RNA-editing hypothesis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0405219101