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¹ Laboratory of Molecular Immunology and ² Laboratory of Mass Spectrometry, ³ Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021

CORRESPONDENCE Michel C. Nussenzweig: nussen{at}mail.rockefeller.edu

Activation-induced cytidine deaminase (AID) is a mutator enzyme that initiates somatic mutation and class switch recombination in B lymphocytes by introducing uracil:guanine mismatches into DNA. Repair pathways process these mismatches to produce point mutations in the Ig variable region or double-stranded DNA breaks in the switch region DNA. However, AID can also produce off-target DNA damage, including mutations in oncogenes. Therefore, stringent regulation of AID is required for maintaining genomic stability during maturation of the antibody response. It has been proposed that AID phosphorylation at serine 38 (S38) regulates its activity, but this has not been tested in vivo. Using a combination of mass spectrometry and immunochemical approaches, we found that in addition to S38, AID is also phosphorylated at position threonine 140 (T140). Mutation of either S38 or T140 to alanine does not impact catalytic activity, but interferes with class switching and somatic hypermutation in vivo. This effect is particularly pronounced in haploinsufficient mice where AID levels are limited. Although S38 is equally important for both processes, T140 phosphorylation preferentially affects somatic mutation, suggesting that posttranslational modification might contribute to the choice between hypermutation and class switching.

© 2008 McBride et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• MacDuff, D. A., Demorest, Z. L., Harris, R. S. (2009). AID can restrict L1 retrotransposition suggesting a dual role in innate and adaptive immunity. Nucleic Acids Res 37: 1854-1867 [Abstract] [Full Text]  
• Cheng, H.-L., Vuong, B. Q., Basu, U., Franklin, A., Schwer, B., Astarita, J., Phan, R. T., Datta, A., Manis, J., Alt, F. W., Chaudhuri, J. (2009). Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice. Proc. Natl. Acad. Sci. USA 106: 2717-2722 [Abstract] [Full Text]  

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