Regulation of Hypermutation by Activation-Induced Cytidine Deaminase Phosphorylation

Activation-induced cytidine deaminase (AID) initiates Ig class switch recombination and somatic hypermutation by producing U:G mismatches in DNA. These mismatches also have the potential to induce DNA damage including double-stranded breaks and chromosome translocations; therefore, strict regulation...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-06, Vol.103 (23), p.8798-8803
Main Authors: McBride, Kevin M., Gazumyan, Anna, Woo, Eileen M., Barreto, Vasco M., Robbiani, Davide F., Chait, Brian T., Nussenzweig, Michel C.
Format: Article
Language:English
Subjects:
AIDS
Amino Acid Sequence
Animals
Antibodies
B lymphocytes
B-Lymphocytes - enzymology
B-Lymphocytes - immunology
Biological Sciences
Cells, Cultured
Cellular immunity
Chromatin
Cytidine Deaminase - chemistry
Cytidine Deaminase - deficiency
Cytidine Deaminase - metabolism
DNA
DNA damage
Fibroblasts - enzymology
Gene expression regulation
Genetic mutation
Genetic recombination
Genomics
Immunoglobulin Class Switching - immunology
Mice
Molecular Sequence Data
Mutation
Phosphorylation
Phosphoserine - metabolism
Proteins
Retroviridae
Somatic Hypermutation, Immunoglobulin - genetics
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Summary:Activation-induced cytidine deaminase (AID) initiates Ig class switch recombination and somatic hypermutation by producing U:G mismatches in DNA. These mismatches also have the potential to induce DNA damage including double-stranded breaks and chromosome translocations; therefore, strict regulation of AID is important for maintaining genomic stability. In addition to transcriptional regulation, it has been proposed that phosphorylation can also modulate AID activity. Using a combination of MS and immunochemical approaches we found that 5-15% of the AID expressed in activated B cells was phosphorylated at serine-38 (p38AID). This form of AID was enriched in the chromatin fraction in activated B cells, suggesting a role for phosphorylation in targeting AID to DNA. Consistent with this idea, serine-38 to alanine mutant AID ($AID^{S38A}$) showed diminished somatic hypermutation activity on artificial and physiological DNA targets. We conclude that a small fraction of AID is phosphorylated in activated B cells and that the modified form contributes disproportionately to hypermutation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0603272103