Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 15 February 2002:
Vol. 295. no. 5558, pp. 1301 - 1306
DOI: 10.1126/science.1067308
Prev | Table of Contents | Next

Reports

Requirement of the Activation-Induced Deaminase (AID) Gene for Immunoglobulin Gene Conversion

Hiroshi Arakawa, Jessica Hauschild, Jean-Marie Buerstedde*

Three phenotypically distinct processes--somatic hypermutation, gene conversion, and switch recombination--remodel the functionally rearranged immunoglobulin (Ig) loci in B cells. Somatic hypermutation and switch recombination have recently been shown to depend on the activation-induced deaminase (AID) gene product. Here, we show that the disruption of the AID gene in the chicken B cell line DT40 completely blocks Ig gene conversion and that this block can be complemented by reintroduction of the AID complementary DNA. This demonstrates that the AID master gene controls all B cell-specific modifications of vertebrate Ig genes.

Department of Cellular Immunology, Heinrich-Pette-Institute, Martinistrasse 52, 20251 Hamburg, Germany.
*   To whom correspondence should be addressed. E-mail: buersted{at}hpi.uni-hamburg.de

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Temporal Regulation of Ig Gene Diversification Revealed by Single-Cell Imaging.
E. C. Ordinario, M. Yabuki, R. P. Larson, and N. Maizels (2009)
J. Immunol. 183, 4545-4553
   Abstract »    Full Text »    PDF »
Bloom DNA Helicase Facilitates Homologous Recombination between Diverged Homologous Sequences.
K. Kikuchi, H. I. Abdel-Aziz, Y. Taniguchi, M. Yamazoe, S. Takeda, and K. Hirota (2009)
J. Biol. Chem. 284, 26360-26367
   Abstract »    Full Text »    PDF »
Progesterone Inhibits Activation-Induced Deaminase by Binding to the Promoter.
S. Pauklin and S. K. Petersen-Mahrt (2009)
J. Immunol. 183, 1238-1244
   Abstract »    Full Text »    PDF »
AID can restrict L1 retrotransposition suggesting a dual role in innate and adaptive immunity.
D. A. MacDuff, Z. L. Demorest, and R. S. Harris (2009)
Nucleic Acids Res. 37, 1854-1867
   Abstract »    Full Text »    PDF »
Molecular mechanism for generation of antibody memory.
V. Shivarov, R. Shinkura, T. Doi, N. A Begum, H. Nagaoka, I.-M. Okazaki, S. Ito, T. Nonaka, K. Kinoshita, and T. Honjo (2009)
Phil Trans R Soc B 364, 569-575
   Abstract »    Full Text »    PDF »
Timing matters: error-prone gap filling and translesion synthesis in immunoglobulin gene hypermutation.
J. E Sale, C. Batters, C. E Edmunds, L. G Phillips, L. J Simpson, and D. Szuts (2009)
Phil Trans R Soc B 364, 595-603
   Abstract »    Full Text »    PDF »
Activation-induced cytidine deaminase-mediated hypermutation in the DT40 cell line.
H. Arakawa and J.-M. Buerstedde (2009)
Phil Trans R Soc B 364, 639-644
   Abstract »    Full Text »    PDF »
Estrogen directly activates AID transcription and function.
S. Pauklin, I. V. Sernandez, G. Bachmann, A. R. Ramiro, and S. K. Petersen-Mahrt (2009)
J. Exp. Med. 206, 99-111
   Abstract »    Full Text »    PDF »
E2A Acts in cis in G1 Phase of Cell Cycle to Promote Ig Gene Diversification.
M. Yabuki, E. C. Ordinario, W. J. Cummings, M. M. Fujii, and N. Maizels (2009)
J. Immunol. 182, 408-415
   Abstract »    Full Text »    PDF »
The 9-1-1 DNA Clamp Is Required for Immunoglobulin Gene Conversion.
A. Saberi, M. Nakahara, J. E. Sale, K. Kikuchi, H. Arakawa, J.-M. Buerstedde, K. Yamamoto, S. Takeda, and E. Sonoda (2008)
Mol. Cell. Biol. 28, 6113-6122
   Abstract »    Full Text »    PDF »
Modulation of immunoglobulin gene conversion frequency and distribution by the histone deacetylase HDAC2 in chicken DT40..
W. Lin, S.-i. Hashimoto, H. Seo, T. Shibata, and K. Ohta (2008)
Genes Cells 13, 255-268
   Abstract »    Full Text »    PDF »
Cutting Edge: A cis-Acting DNA Element Targets AID-Mediated Sequence Diversification to the Chicken Ig Light Chain Gene Locus.
N. Kothapalli, D. D. Norton, and S. D. Fugmann (2008)
J. Immunol. 180, 2019-2023
   Abstract »    Full Text »    PDF »
Regulation of histone H4 acetylation by transcription factor E2A in Ig gene conversion.
H. Kitao, M. Kimura, K. Yamamoto, H. Seo, K. Namikoshi, Y. Agata, K. Ohta, and M. Takata (2008)
Int. Immunol. 20, 277-284
   Abstract »    Full Text »    PDF »
B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins.
J. Hauser, N. Sveshnikova, A. Wallenius, S. Baradaran, J. Saarikettu, and T. Grundstrom (2008)
PNAS 105, 1267-1272
   Abstract »    Full Text »    PDF »
Protein evolution by hypermutation and selection in the B cell line DT40.
H. Arakawa, H. Kudo, V. Batrak, R. B. Caldwell, M. A. Rieger, J. W. Ellwart, and J.-M. Buerstedde (2008)
Nucleic Acids Res. 36, e1
   Abstract »    Full Text »    PDF »
Dependence of antibody gene diversification on uracil excision.
J. M. Di Noia, G. T. Williams, D. T.Y. Chan, J.-M. Buerstedde, G. S. Baldwin, and M. S. Neuberger (2007)
J. Exp. Med. 204, 3209-3219
   Abstract »    Full Text »    PDF »
Single-Stranded DNA Structure and Positional Context of the Target Cytidine Determine the Enzymatic Efficiency of AID.
M. Larijani and A. Martin (2007)
Mol. Cell. Biol. 27, 8038-8048
   Abstract »    Full Text »    PDF »
Localization and Differential Expression of Activation-Induced Cytidine Deaminase in the Amphibian Xenopus upon Antigen Stimulation and during Early Development.
S. Marr, H. Morales, A. Bottaro, M. Cooper, M. Flajnik, and J. Robert (2007)
J. Immunol. 179, 6783-6789
   Abstract »    Full Text »    PDF »
Subcellular distribution of human RDM1 protein isoforms and their nucleolar accumulation in response to heat shock and proteotoxic stress.
L. Messaoudi, Y.-G. Yang, A. Kinomura, D. A. Stavreva, G. Yan, M.-L. Bortolin-Cavaille, H. Arakawa, J.-M. Buerstedde, P. Hainaut, J. Cavaille, et al. (2007)
Nucleic Acids Res. 35, 6571-6587
   Abstract »    Full Text »    PDF »
Activation-induced Cytidine Deaminase-mediated Sequence Diversification Is Transiently Targeted to Newly Integrated DNA Substrates.
S. Y. Yang, S. D. Fugmann, H. S. Gramlich, and D. G. Schatz (2007)
J. Biol. Chem. 282, 25308-25313
   Abstract »    Full Text »    PDF »
Analysis of 6912 Unselected Somatic Hypermutations in Human VDJ Rearrangements Reveals Lack of Strand Specificity and Correlation between Phase II Substitution Rates and Distance to the Nearest 3' Activation-Induced Cytidine Deaminase Target.
L. Ohm-Laursen and T. Barington (2007)
J. Immunol. 178, 4322-4334
   Abstract »    Full Text »    PDF »
Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma.
G. Lenz, I. Nagel, R. Siebert, A. V. Roschke, W. Sanger, G. W. Wright, S. S. Dave, B. Tan, H. Zhao, A. Rosenwald, et al. (2007)
J. Exp. Med. 204, 633-643
   Abstract »    Full Text »    PDF »
Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice.
A. Kotani, N. Kakazu, T. Tsuruyama, I.-m. Okazaki, M. Muramatsu, K. Kinoshita, H. Nagaoka, D. Yabe, and T. Honjo (2007)
PNAS 104, 1616-1620
   Abstract »    Full Text »    PDF »
Control of gene conversion and somatic hypermutation by immunoglobulin promoter and enhancer sequences.
S. Y. Yang, S. D. Fugmann, and D. G. Schatz (2006)
J. Exp. Med. 203, 2919-2928
   Abstract »    Full Text »    PDF »
NHEJ-deficient DT40 cells have increased levels of immunoglobulin gene conversion: evidence for a double strand break intermediate.
E. S. Tang and A. Martin (2006)
Nucleic Acids Res. 34, 6345-6351
   Abstract »    Full Text »    PDF »
VH Replacement Rescues Progenitor B Cells with Two Nonproductive VDJ Alleles.
J. Lutz, W. Muller, and H.-M. Jack (2006)
J. Immunol. 177, 7007-7014
   Abstract »    Full Text »    PDF »
Role for RAD18 in Homologous Recombination in DT40 Cells.
D. Szuts, L. J. Simpson, S. Kabani, M. Yamazoe, and J. E. Sale (2006)
Mol. Cell. Biol. 26, 8032-8041
   Abstract »    Full Text »    PDF »
Involvement of Rad18 in somatic hypermutation.
J. Bachl, I. Ertongur, and B. Jungnickel (2006)
PNAS 103, 12081-12086
   Abstract »    Full Text »    PDF »
Identification of a Specific Domain Required for Dimerization of Activation-induced Cytidine Deaminase.
J. Wang, R. Shinkura, M. Muramatsu, H. Nagaoka, K. Kinoshita, and T. Honjo (2006)
J. Biol. Chem. 281, 19115-19123
   Abstract »    Full Text »    PDF »
Structural Phylogenetic Analysis of Activation-Induced Deaminase Function.
H. T. Ichikawa, M. P. Sowden, A. T. Torelli, J. Bachl, P. Huang, G. S. C. Dance, S. H. Marr, J. Robert, J. E. Wedekind, H. C. Smith, et al. (2006)
J. Immunol. 177, 355-361
   Abstract »    Full Text »    PDF »
E2A Expression Stimulates Ig Hypermutation.
U. Schoetz, M. Cervelli, Y.-D. Wang, P. Fiedler, and J.-M. Buerstedde (2006)
J. Immunol. 177, 395-400
   Abstract »    Full Text »    PDF »
Impaired class switch recombination (CSR) in Waldenstrom macroglobulinemia (WM) despite apparently normal CSR machinery.
J. Kriangkum, B. J. Taylor, E. Strachan, M. J. Mant, T. Reiman, A. R. Belch, and L. M. Pilarski (2006)
Blood 107, 2920-2927
   Abstract »    Full Text »    PDF »
The Nucleotide Targets of Somatic Mutation and the Role of Selection in Immunoglobulin Heavy Chains of a Teleost Fish.
F. Yang, G. C. Waldbieser, and C. J. Lobb (2006)
J. Immunol. 176, 1655-1667
   Abstract »    Full Text »    PDF »
Genetic manipulation of an exogenous non-immunoglobulin protein by gene conversion machinery in a chicken B cell line.
N. Kanayama, K. Todo, S. Takahashi, M. Magari, and H. Ohmori (2006)
Nucleic Acids Res. 34, e10
   Abstract »    Full Text »    PDF »
Evolution of class switch recombination function in fish activation-induced cytidine deaminase, AID.
K. Wakae, B. G. Magor, H. Saunders, H. Nagaoka, A. Kawamura, K. Kinoshita, T. Honjo, and M. Muramatsu (2006)
Int. Immunol. 18, 41-47
   Abstract »    Full Text »    PDF »
Uracil DNA Glycosylase Disruption Blocks Ig Gene Conversion and Induces Transition Mutations.
H. Saribasak, N. N. Saribasak, F. M. Ipek, J. W. Ellwart, H. Arakawa, and J.-M. Buerstedde (2006)
J. Immunol. 176, 365-371
   Abstract »    Full Text »    PDF »
Sequence Transfers between Variable Regions in a Mouse Antibody Transgene Can Occur by Gene Conversion.
N. D'Avirro, D. Truong, B. Xu, and E. Selsing (2005)
J. Immunol. 175, 8133-8137
   Abstract »    Full Text »    PDF »
Activation-induced deaminase cloning, localization, and protein extraction from young VH-mutant rabbit appendix.
G. Yang, H. Obiakor, R. K. Sinha, B. A. Newman, B. L. Hood, T. P. Conrads, T. D. Veenstra, and R. G. Mage (2005)
PNAS 102, 17083-17088
   Abstract »    Full Text »    PDF »
Common Variable Immunodeficiency: Test Indications and Interpretations.
C. R. Weiler and J. L. Bankers-Fulbright (2005)
Mayo Clin. Proc. 80, 1187-1200
   Abstract »    PDF »
Fen-1 Facilitates Homologous Recombination by Removing Divergent Sequences at DNA Break Ends.
K. Kikuchi, Y. Taniguchi, A. Hatanaka, E. Sonoda, H. Hochegger, N. Adachi, Y. Matsuzaki, H. Koyama, D. C. van Gent, M. Jasin, et al. (2005)
Mol. Cell. Biol. 25, 6948-6955
   Abstract »    Full Text »    PDF »
A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression.
A. Kotani, I.-m. Okazaki, M. Muramatsu, K. Kinoshita, N. A. Begum, T. Nakajima, H. Saito, and T. Honjo (2005)
PNAS 102, 4506-4511
   Abstract »    Full Text »    PDF »
RDM1, a Novel RNA Recognition Motif (RRM)-containing Protein Involved in the Cell Response to Cisplatin in Vertebrates.
S. Hamimes, H. Arakawa, A. Z. Stasiak, A. M. Kierzek, S. Hirano, Y.-G. Yang, M. Takata, A. Stasiak, J.-M. Buerstedde, and E. Van Dyck (2005)
J. Biol. Chem. 280, 9225-9235
   Abstract »    Full Text »    PDF »
DNA cleavage in immunoglobulin somatic hypermutation depends on de novo protein synthesis but not on uracil DNA glycosylase.
H. Nagaoka, S. Ito, M. Muramatsu, M. Nakata, and T. Honjo (2005)
PNAS 102, 2022-2027
   Abstract »    Full Text »    PDF »
Similar Effects of Brca2 Truncation and Rad51 Paralog Deficiency on Immunoglobulin V Gene Diversification in DT40 Cells Support an Early Role for Rad51 Paralogs in Homologous Recombination.
A. Hatanaka, M. Yamazoe, J. E. Sale, M. Takata, K. Yamamoto, H. Kitao, E. Sonoda, K. Kikuchi, Y. Yonetani, and S. Takeda (2005)
Mol. Cell. Biol. 25, 1124-1134
   Abstract »    Full Text »    PDF »
Fanconi Anemia Protein FANCD2 Promotes Immunoglobulin Gene Conversion and DNA Repair through a Mechanism Related to Homologous Recombination.
K. Yamamoto, S. Hirano, M. Ishiai, K. Morishima, H. Kitao, K. Namikoshi, M. Kimura, N. Matsushita, H. Arakawa, J.-M. Buerstedde, et al. (2005)
Mol. Cell. Biol. 25, 34-43
   Abstract »    Full Text »    PDF »
De novo protein synthesis is required for activation-induced cytidine deaminase-dependent DNA cleavage in immunoglobulin class switch recombination.
N. A. Begum, K. Kinoshita, M. Muramatsu, H. Nagaoka, R. Shinkura, and T. Honjo (2004)
PNAS 101, 13003-13007
   Abstract »    Full Text »    PDF »
Activation-induced Cytosine Deaminase (AID) Is Actively Exported out of the Nucleus but Retained by the Induction of DNA Breaks.
S. S. Brar, M. Watson, and M. Diaz (2004)
J. Biol. Chem. 279, 26395-26401
   Abstract »    Full Text »    PDF »
Advantages and Disadvantages of Cytidine Deamination.
M. Cascalho (2004)
J. Immunol. 172, 6513-6518
   Abstract »    Full Text »    PDF »
Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-{kappa}B activation pathways.
B. Zarnegar, J. Q. He, G. Oganesyan, A. Hoffmann, D. Baltimore, and G. Cheng (2004)
PNAS 101, 8108-8113
   Abstract »    Full Text »    PDF »
The structure of a yeast RNA-editing deaminase provides insight into the fold and function of activation-induced deaminase and APOBEC-1.
K. Xie, M. P. Sowden, G. S. C. Dance, A. T. Torelli, H. C. Smith, and J. E. Wedekind (2004)
PNAS 101, 8114-8119
   Abstract »    Full Text »    PDF »
Immunoglobulin class-switch recombination in mice devoid of any S{micro} tandem repeat.
A. A. Khamlichi, F. Glaudet, Z. Oruc, V. Denis, M. Le Bert, and M. Cogne (2004)
Blood 103, 3828-3836
   Abstract »    Full Text »    PDF »
DNA Substrate Length and Surrounding Sequence Affect the Activation-induced Deaminase Activity at Cytidine.
K. Yu, F.-T. Huang, and M. R. Lieber (2004)
J. Biol. Chem. 279, 6496-6500
   Abstract »    Full Text »    PDF »
Activation-induced cytidine deaminase shuttles between nucleus and cytoplasm like apolipoprotein B mRNA editing catalytic polypeptide 1.
S. Ito, H. Nagaoka, R. Shinkura, N. Begum, M. Muramatsu, M. Nakata, and T. Honjo (2004)
PNAS 101, 1975-1980
   Abstract »    Full Text »    PDF »
Role of Commensal Bacteria in Development of Gut-Associated Lymphoid Tissues and Preimmune Antibody Repertoire.
K.-J. Rhee, P. Sethupathi, A. Driks, D. K. Lanning, and K. L. Knight (2004)
J. Immunol. 172, 1118-1124
   Abstract »    Full Text »    PDF »
The generation of antibody diversity through somatic hypermutation and class switch recombination.
Z. Li, C. J. Woo, M. D. Iglesias-Ussel, D. Ronai, and M. D. Scharff (2004)
Genes & Dev. 18, 1-11
   Full Text »    PDF »
RNA-editing cytidine deaminase Apobec-1 is unable to induce somatic hypermutation in mammalian cells.
T. Eto, K. Kinoshita, K. Yoshikawa, M. Muramatsu, and T. Honjo (2003)
PNAS 100, 12895-12898
   Abstract »    Full Text »    PDF »
Conditional human VEGF-mediated vascularization in chicken embryos using a novel temperature-inducible gene regulation (TIGR) system.
W. Weber, R. R. Marty, N. Link, M. Ehrbar, B. Keller, C. C. Weber, A. H. Zisch, C. Heinzen, V. Djonov, and M. Fussenegger (2003)
Nucleic Acids Res. 31, e69
   Abstract »    Full Text »    PDF »
Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations.
A. Sohail, J. Klapacz, M. Samaranayake, A. Ullah, and A. S. Bhagwat (2003)
Nucleic Acids Res. 31, 2990-2994
   Abstract »    Full Text »    PDF »
AID Mediates Hypermutation by Deaminating Single Stranded DNA.
S. K. Dickerson, E. Market, E. Besmer, and F. N. Papavasiliou (2003)
J. Exp. Med. 197, 1291-1296
   Abstract »    Full Text »    PDF »
Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas.
J. Greeve, A. Philipsen, K. Krause, W. Klapper, K. Heidorn, B. E. Castle, J. Janda, K. B. Marcu, and R. Parwaresch (2003)
Blood 101, 3574-3580
   Abstract »    Full Text »    PDF »
Diversity of the Immune Repertoire and Immunoregulation.
R. S. Schwartz (2003)
N. Engl. J. Med. 348, 1017-1026
   Full Text »    PDF »
Accessibility control and machinery of immunoglobulin class switch recombination.
K. Zhang (2003)
J. Leukoc. Biol. 73, 323-332
   Abstract »    Full Text »    PDF »
Human Activation-Induced Cytidine Deaminase Is Induced by IL-4 and Negatively Regulated by CD45: Implication of CD45 as a Janus Kinase Phosphatase in Antibody Diversification.
C. Zhou, A. Saxon, and K. Zhang (2003)
J. Immunol. 170, 1887-1893
   Abstract »    Full Text »    PDF »
Bcl-2 Rescues the Germinal Center Response But Does Not Alter the V Gene Somatic Hypermutation Spectrum in MSH2-Deficient Mice.
B. Alabyev and T. Manser (2002)
J. Immunol. 169, 3819-3824
   Abstract »    Full Text »    PDF »
Somatic hypermutation of the AID transgene in B and non-B cells.
A. Martin and M. D. Scharff (2002)
PNAS 99, 12304-12308
   Abstract »    Full Text »    PDF »
Reconstitution of mRNA Editing in Yeast Using a Gal4-ApoB-Gal80 Fusion Transcript as the Selectable Marker.
H. Lellek, S. Welker, I. Diehl, R. Kirsten, and J. Greeve (2002)
J. Biol. Chem. 277, 23638-23644
   Abstract »    Full Text »    PDF »
AID Enzyme-Induced Hypermutation in an Actively Transcribed Gene in Fibroblasts.
K. Yoshikawa, I.-m. Okazaki, T. Eto, K. Kinoshita, M. Muramatsu, H. Nagaoka, and T. Honjo (2002)
Science 296, 2033-2036
   Abstract »    Full Text »    PDF »
The Function of AID in Somatic Mutation and Class Switch Recombination: Upstream or Downstream of DNA Breaks.
K. F. Chua, F. W. Alt, and J. P. Manis (2002)
J. Exp. Med. 195, F37-F41
   Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)