Chapter 5 DNA Targets of AID. Evolutionary Link Between Antibody Somatic Hypermutation and Class Switch Recombination

Advances in Immunology

Volumn 101, Issue C, 2009, Pages 163-189

  Hackney, Jason A ^a   Misaghi, Shahram ^a   Senger, Kate ^a   Garris, Christopher ^a   Sun, Yonglian ^a   Lorenzo, Maria N ^a   Zarrin, Ali A ^b  

^a Immunology Discovery Group ^*

^b GENENTECH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATION INDUCED CYTIDINE DEAMINASE; DOUBLE STRANDED DNA; AICDA (ACTIVATION INDUCED CYTIDINE DEAMINASE); AICDA (ACTIVATION-INDUCED CYTIDINE DEAMINASE); CYTIDINE DEAMINASE; IMMUNOGLOBULIN;

DNA STRAND BREAKAGE; GENE DUPLICATION; GENE SEQUENCE; GENE TARGETING; GENE TRANSLOCATION; PRIORITY JOURNAL; REVIEW; SOMATIC HYPERMUTATION; ANIMAL; B LYMPHOCYTE; EVOLUTION; GENE REARRANGEMENT; GENETICS; HUMAN; IMMUNOGLOBULIN GENE; IMMUNOLOGY; METABOLISM;

ANIMALS; B-LYMPHOCYTES; CYTIDINE DEAMINASE; EVOLUTION; GENES, IMMUNOGLOBULIN; HUMANS; IMMUNOGLOBULIN CLASS SWITCHING; IMMUNOGLOBULINS; SOMATIC HYPERMUTATION, IMMUNOGLOBULIN;

EID: 60749084171     PISSN: 00652776     EISSN: 15578445     Source Type: Book Series    
DOI: 10.1016/S0065-2776(08)01005-5     Document Type: Review

References (111)

1. Bachl J., and Olsson C. Hypermutation targets a green fluorescent protein-encoding transgene in the presence of immunoglobulin enhancers. Eur. J. Immunol. 29 (1999) 1383
2. Barreto V.M., Pan-Hammarstrom Q., Zhao Y., Hammarstrom L., Misulovin Z., and Nussenzweig M.C. AID from bony fish catalyzes class switch recombination. J. Exp. Med. 202 (2005) 733
3. Betz A.G., Milstein C., Gonzalez-Fernandez A., Pannell R., Larson T., and Neuberger M.S. Elements regulating somatic hypermutation of an immunoglobulin kappa gene: Critical role for the intron enhancer/matrix attachment region. Cell 77 (1994) 239
4. Bottaro A., Lansford R., Xu L., Zhang J., Rothman P., and Alt F.W. S region transcription per se promotes basal IgE class switch recombination but additional factors regulate the efficiency of the process. EMBO J. 13 (1994) 665
5. Bransteitter R., Pham P., Calabrese P., and Goodman M.F. Biochemical analysis of hypermutational targeting by wild type and mutant activation-induced cytidine deaminase. J. Biol. Chem. 279 (2004) 51612
6. Bransteitter R., Pham P., Scharff M.D., and Goodman M.F. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc. Natl. Acad. Sci. USA 100 (2003) 4102
7. Chaudhuri J., and Jasin M. Antibodies get a break. Science 315 (2007) 335
8. Chaudhuri J., Khuong C., and Alt F.W. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430 (2004) 992
9. Chaudhuri J., Tian M., Khuong C., Chua K., Pinaud E., and Alt F.W. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422 (2003) 726
10. Chen J., Lansford R., Stewart V., Young F., and Alt F.W. RAG-2-deficient blastocyst complementation: An assay of gene function in lymphocyte development. Proc. Natl. Acad. Sci. USA 90 (1993) 4528
11. Cogne M., Lansford R., Bottaro A., Zhang J., Gorman J., Young F., Cheng H.L., and Alt F.W. A class switch control region at the 3′ end of the immunoglobulin heavy chain locus. Cell 77 (1994) 737
12. Di Noia J., and Neuberger M.S. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419 (2002) 43
13. Di Noia J.M., and Neuberger M.S. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76 (2007) 1
14. Diaz M., and Flajnik M.F. Evolution of somatic hypermutation and gene conversion in adaptive immunity. Immunol. Rev. 162 (1998) 13
15. Dorner T., Foster S.J., Farner N.L., and Lipsky P.E. Somatic hypermutation of human immunoglobulin heavy chain genes: Targeting of RGYW motifs on both DNA strands. Eur. J. Immunol. 28 (1998) 3384
16. Dudley D.D., Chaudhuri J., Bassing C.H., and Alt F.W. Mechanism and control of V(D)J recombination versus class switch recombination: Similarities and differences. Adv. Immunol. 86 (2005) 43
17. Dudley D.D., Manis J.P., Zarrin A.A., Kaylor L., Tian M., and Alt F.W. Internal IgH class switch region deletions are position-independent and enhanced by AID expression. Proc. Natl. Acad. Sci. USA 99 (2002) 9984
18. Dunnick W., Hertz G.Z., Scappino L., and Gritzmacher C. DNA sequences at immunoglobulin switch region recombination sites. Nucleic Acids Res. 21 (1993) 365
19. Dunnick W.A., Shi J., Graves K.A., and Collins J.T. Germline transcription and switch recombination of a transgene containing the entire H chain constant region locus: Effect of a mutation in a STAT6 binding site in the gamma 1 promoter. J. Immunol. 173 (2004) 5531
20. Duquette M.L., Huber M.D., and Maizels N. G-rich proto-oncogenes are targeted for genomic instability in B-cell lymphomas. Cancer Res. 67 (2007) 2586
21. Duquette M.L., Pham P., Goodman M.F., and Maizels N. AID binds to transcription-induced structures in c-MYC that map to regions associated with translocation and hypermutation. Oncogene 24 (2005) 5791
22. Flajnik M.F. Comparative analyses of immunoglobulin genes: Surprises and portents. Nat. Rev. Immunol. 2 (2002) 688
23. Franco S., Gostissa M., Zha S., Lombard D.B., Murphy M.M., Zarrin A.A., Yan C., Tepsuporn S., Morales J.C., Adams M.M., Lou Z., Bassing C.H., et al. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell 21 (2006) 201
24. Gu H., Zou Y.R., and Rajewsky K. Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell 73 (1993) 1155
25. Honjo T., Kinoshita K., and Muramatsu M. Molecular mechanism of class switch recombination: Linkage with somatic hypermutation. Annu. Rev. Immunol. 20 (2002) 165
26. Hsu E., Pulham N., Rumfelt L.L., and Flajnik M.F. The plasticity of immunoglobulin gene systems in evolution. Immunol. Rev. 210 (2006) 8
27. Huang F.T., Yu K., Balter B.B., Selsing E., Oruc Z., Khamlichi A.A., Hsieh C.L., and Lieber M.R. Sequence dependence of chromosomal R-loops at the immunoglobulin heavy-chain Smu class switch region. Mol. Cell. Biol. 27 (2007) 5921
28. Jacquier A., and Dujon B. An intron-encoded protein is active in a gene conversion process that spreads an intron into a mitochondrial gene. Cell 41 (1985) 383
29. Jiang C., Foley J., Clayton N., Kissling G., Jokinen M., Herbert R., and Diaz M. Abrogation of lupus nephritis in activation-induced deaminase-deficient MRL/lpr mice. J. Immunol. 178 (2007) 7422
30. Jiang C., Zhao M.L., and Diaz M. Activation-induced deaminase heterozygous MRL/lpr mice are delayed in the production of high-affinity pathogenic antibodies and in the development of lupus nephritis. Immunology 10 (2008) 1365
31. Jung S., Rajewsky K., and Radbruch A. Shutdown of class switch recombination by deletion of a switch region control element. Science 259 (1993) 984
32. Kenter A.L., Wuerffel R., Dominguez C., Shanmugam A., and Zhang H. Mapping of a functional recombination motif that defines isotype specificity for mu-->gamma3 switch recombination implicates NF-kappaB p50 as the isotype-specific switching factor. J. Exp. Med. 199 (2004) 617
33. Khamlichi A.A., Glaudet F., Oruc Z., Denis V., Le Bert M., and Cogne M. Immunoglobulin class-switch recombination in mice devoid of any S mu tandem repeat. Blood 103 (2004) 3828
34. Kinoshita K., Tashiro J., Tomita S., Lee C.G., and Honjo T. Target specificity of immunoglobulin class switch recombination is not determined by nucleotide sequences of S regions. Immunity 9 (1998) 849
35. Klein U., and Dalla-Favera R. Germinal centres: Role in B-cell physiology and malignancy. Nat. Rev. Immunol. 8 (2008) 22
36. Larijani M., and Martin A. Single-stranded DNA structure and positional context of the target cytidine determine the enzymatic efficiency of AID. Mol. Cell. Biol. 27 (2007) 8038
37. Larijani M., Petrov A.P., Kolenchenko O., Berru M., Krylov S.N., and Martin A. AID associates with single-stranded DNA with high affinity and a long complex half-life in a sequence-independent manner. Mol. Cell. Biol. 27 (2007) 20
38. Liu M., Duke J.L., Richter D.J., Vinuesa C.G., Goodnow C.C., Kleinstein S.H., and Schatz D.G. Two levels of protection for the B cell genome during somatic hypermutation. Nature 451 (2008) 841
39. Luby T.M., Schrader C.E., Stavnezer J., and Selsing E. The mu switch region tandem repeats are important, but not required, for antibody class switch recombination. J. Exp. Med. 193 (2001) 159
40. Lundqvist M.L., Middleton D.L., Hazard S., and Warr G.W. The immunoglobulin heavy chain locus of the duck. Genomic organization and expression of D, J, and C region genes. J. Biol. Chem. 276 (2001) 46729
41. Lundqvist M.L., Middleton D.L., Radford C., Warr G.W., and Magor K.E. Immunoglobulins of the non-galliform birds: Antibody expression and repertoire in the duck. Dev. Comp. Immunol. 30 (2006) 93
42. Maizels N. Immunoglobulin gene diversification. Annu. Rev. Genet. 39 (2005) 23
43. Manis J.P., Dudley D., Kaylor L., and Alt F.W. IgH class switch recombination to IgG1 in DNA-PKcs-deficient B cells. Immunity 16 (2002) 607
44. Manis J.P., Morales J.C., Xia Z., Kutok J.L., Alt F.W., and Carpenter P.B. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat. Immunol. 5 (2004) 481
45. Martin A., and Scharff M.D. AID and mismatch repair in antibody diversification. Nat. Rev. Immunol. 2 (2002) 605
46. Martomo S.A., and Gearhart P.J. Somatic hypermutation: Subverted DNA repair. Curr. Opin. Immunol. 18 (2006) 243
47. Meffre E., Catalan N., Seltz F., Fischer A., Nussenzweig M.C., and Durandy A. Somatic hypermutation shapes the antibody repertoire of memory B cells in humans. J. Exp. Med. 194 (2001) 375
48. Mietzner B., Tsuiji M., Scheid J., Velinzon K., Tiller T., Abraham K., Gonzalez J.B., Pascual V., Stichweh D., Wardemann H., and Nussenzweig M.C. Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors. Proc. Natl. Acad. Sci. USA 105 (2008) 9727
49. Migliazza A., Martinotti S., Chen W., Fusco C., Ye B.H., Knowles D.M., Offit K., Chaganti R.S., and Dalla-Favera R. Frequent somatic hypermutation of the 5′ noncoding region of the BCL6 gene in B-cell lymphoma. Proc. Natl. Acad. Sci. USA 92 (1995) 12520
50. Mowatt M., Dery C., and Dunnick W. Unique sequences are interspersed among tandemly repeated elements in the murine gamma 1 switch segment. Nucleic Acids Res. 13 (1985) 225
51. Muramatsu M., Kinoshita K., Fagarasan S., Yamada S., Shinkai Y., and Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102 (2000) 553
52. Mussmann R., Courtet M., Schwager J., and Du Pasquier L. Microsites for immunoglobulin switch recombination breakpoints from Xenopus to mammals. Eur. J. Immunol. 27 (1997) 2610
53. Nambu Y., Sugai M., Gonda H., Lee C.G., Katakai T., Agata Y., Yokota Y., and Shimizu A. Transcription-coupled events associating with immunoglobulin switch region chromatin. Science 302 (2003) 2137
54. Neuberger M.S. Antibody diversification by somatic mutation: From Burnet onwards. Immunol. Cell. Biol. 86 (2008) 124
55. Ohta Y., and Flajnik M. IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates. Proc. Natl. Acad. Sci. USA 103 (2006) 10723
56. Pan Q., Rabbani H., and Hammarstrom L. Characterization of human gamma 4 switch region polymorphisms suggests a meiotic recombinational hot spot within the Ig locus: influence of S region length on IgG4 production. J. Immunol. 161 (1998) 3520
57. Pasqualucci L., Neumeister P., Goossens T., Nanjangud G., Chaganti R.S., Kuppers R., and Dalla-Favera R. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412 (2001) 341
58. Perlot T., Alt F.W., Bassing C.H., Suh H., and Pinaud E. Elucidation of IgH intronic enhancer functions via germ-line deletion. Proc. Natl. Acad. Sci. USA 102 (2005) 14362
59. Petersen S., Casellas R., Reina-San-Martin B., Chen H.T., Difilippantonio M.J., Wilson P.C., Hanitsch L., Celeste A., Muramatsu M., Pilch D.R., et al. AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching. Nature 414 (2001) 660
60. Petersen-Mahrt S.K., Harris R.S., and Neuberger M.S. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418 (2002) 99
61. Pham P., Bransteitter R., Petruska J., and Goodman M.F. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 424 (2003) 103
62. Pham P., Smolka M.B., Calabrese P., Landolph A., Zhang K., Zhou H., and Goodman M.F. Impact of phosphorylation and phosphorylation-null mutants on the activity and deamination specificity of activation-induced cytidine deaminase. J. Biol. Chem. 283 (2008) 17428
63. Pinaud E., Khamlichi A.A., Le Morvan C., Drouet M., Nalesso V., Le Bert M., and Cogne M. Localization of the 3′ IgH locus elements that effect long-distance regulation of class switch recombination. Immunity 15 (2001) 187
64. Rada C., Di Noia J.M., and Neuberger M.S. Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation. Mol. Cell. 16 (2004) 163
65. Rada C., Williams G.T., Nilsen H., Barnes D.E., Lindahl T., and Neuberger M.S. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr. Biol. 12 (2002) 1748
66. Ramiro A.R., Jankovic M., Callen E., Difilippantonio S., Chen H.T., McBride K.M., Eisenreich T.R., Chen J., Dickins R.A., Lowe S.W., et al. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 440 (2006) 105
67. Ramiro A.R., Jankovic M., Eisenreich T., Difilippantonio S., Chen-Kiang S., Muramatsu M., Honjo T., Nussenzweig A., and Nussenzweig M.C. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118 (2004) 431
68. Ramiro A.R., Stavropoulos P., Jankovic M., and Nussenzweig M.C. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat. Immunol. 4 (2003) 452
69. Reina-San-Martin B., Difilippantonio S., Hanitsch L., Masilamani R.F., Nussenzweig A., and Nussenzweig M.C. H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation. J. Exp. Med. 197 (2003) 1767
70. Revy P., Muto T., Levy Y., Geissmann F., Plebani A., Sanal O., Catalan N., Forveille M., Dufourcq-Labelouse R., Gennery A., et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102 (2000) 565
71. Rogozin I.B., and Diaz M. Cutting edge: DGYW/WRCH is a better predictor of mutability at G:C bases in Ig hypermutation than the widely accepted RGYW/WRCY motif and probably reflects a two-step activation-induced cytidine deaminase-triggered process. J. Immunol. 172 (2004) 3382
72. Roy D., Yu K., and Lieber M.R. The Mechanism of R-Loop Formation at Immunoglobulin Class Switch Sequences. Mol. Cell. Biol. 28 (2007) 50
73. Rush J.S., Fugmann S.D., and Schatz D.G. Staggered AID-dependent DNA double strand breaks are the predominant DNA lesions targeted to S mu in Ig class switch recombination. Int. Immunol. 16 (2004) 549
74. Sakai E., Bottaro A., Davidson L., Sleckman B.P., and Alt F.W. Recombination and transcription of the endogenous Ig heavy chain locus is effected by the Ig heavy chain intronic enhancer core region in the absence of the matrix attachment regions. Proc. Natl. Acad. Sci. USA 96 (1999) 1526
75. Schrader C.E., Bradley S.P., Vardo J., Mochegova S.N., Flanagan E., and Stavnezer J. Mutations occur in the Ig Smu region but rarely in Sgamma regions prior to class switch recombination. EMBO J. 22 (2003) 5893
76. Schrader C.E., Guikema J.E., Linehan E.K., Selsing E., and Stavnezer J. Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair. J. Immunol. 179 (2007) 6064
77. Schrader C.E., Linehan E.K., Mochegova S.N., Woodland R.T., and Stavnezer J. Inducible DNA breaks in Ig S regions are dependent on AID and UNG. J. Exp. Med. 202 (2005) 561
78. Seidl K.J., Bottaro A., Vo A., Zhang J., Davidson L., and Alt F.W. An expressed neo(r) cassette provides required functions of the 1gamma2b exon for class switching. Int. Immunol. 10 (1998) 1683
79. Seidl K.J., Manis J.P., Bottaro A., Zhang J., Davidson L., Kisselgof A., Oettgen H., and Alt F.W. Position-dependent inhibition of class-switch recombination by PGK-neor cassettes inserted into the immunoglobulin heavy chain constant region locus. Proc. Natl. Acad. Sci. USA 96 (1999) 3000
80. Shen H.M., Peters A., Baron B., Zhu X., and Storb U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280 (1998) 1750
81. Shinkura R., Tian M., Smith M., Chua K., Fujiwara Y., and Alt F.W. The influence of transcriptional orientation on endogenous switch region function. Nat. Immunol. 4 (2003) 435
82. Sohail A., Klapacz J., Samaranayake M., Ullah A., and Bhagwat A.S. Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations. Nucleic Acids Res. 31 (2003) 2990
83. Stavnezer J., and Amemiya C.T. Evolution of isotype switching. Semin. Immunol. 16 (2004) 257
84. Storb U., Peters A., Kim N., Shen H.M., Bozek G., Michael N., Hackett Jr. J., Klotz E., Reynolds J.D., Loeb L.A., and Martin T.E. Molecular aspects of somatic hypermutation of immunoglobulin genes. Cold Spring Harb Symp Quant Biol. 64 (1999) 227
85. Storb U., and Stavnezer J. Immunoglobulin genes: generating diversity with AID and UNG. Curr. Biol. 12 (2002) R725
86. Szurek P., Petrini J., and Dunnick W. Complete nucleotide sequence of the murine gamma 3 switch region and analysis of switch recombination sites in two gamma 3-expressing hybridomas. J. Immunol. 135 (1985) 620
87. Tian M., and Alt F.W. Transcription-induced cleavage of immunoglobulin switch regions by nucleotide excision repair nucleases in vitro. J. Biol. Chem. 275 (2000) 24163
88. Unniraman S., and Schatz D.G. Strand-biased spreading of mutations during somatic hypermutation. Science 317 (2007) 1227
89. Vernersson M., Aveskogh M., Munday B., and Hellman L. Evidence for an early appearance of modern post-switch immunoglobulin isotypes in mammalian evolution (II); cloning of IgE, IgG1 and IgG2 from a monotreme, the duck-billed platypus, Ornithorhynchus anatinus. Eur. J. Immunol. 32 (2002) 2145
90. Wakae K., Magor B.G., Saunders H., Nagaoka H., Kawamura A., Kinoshita K., Honjo T., and Muramatsu M. Evolution of class switch recombination function in fish activation-induced cytidine deaminase, AID. Int. Immunol. 18 (2006) 41
91. Wang C.L., Harper R.A., and Wabl M. Genome-wide somatic hypermutation. Proc. Natl. Acad. Sci. USA 101 (2004) 7352
92. Ward I.M., Reina-San-Martin B., Olaru A., Minn K., Tamada K., Lau J.S., Cascalho M., Chen L., Nussenzweig A., Livak F., et al. 53BP1 is required for class switch recombination. J. Cell. Biol. 165 (2004) 459
93. Wardemann H., and Nussenzweig M.C. B-cell self-tolerance in humans. Adv. Immunol. 95 (2007) 83
94. Wardemann H., Yurasov S., Schaefer A., Young J.W., Meffre E., and Nussenzweig M.C. Predominant autoantibody production by early human B cell precursors. Science 301 (2003) 1374
95. Warren W.C., Hillier L.W., Marshall Graves J.A., Birney E., Ponting C.P., Grutzner F., Belov K., Miller W., Clarke L., Chinwalla A.T., et al. Genome analysis of the platypus reveals unique signatures of evolution. Nature 455 (2008) 256
96. Wuerffel R., Wang L., Grigera F., Manis J., Selsing E., Perlot T., Alt F.W., Cogne M., Pinaud E., and Kenter A.L. S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity 27 (2007) 711
97. Wuerffel R.A., Du J., Thompson R.J., and Kenter A.L. Ig Sgamma3 DNA-specifc double strand breaks are induced in mitogen-activated B cells and are implicated in switch recombination. J. Immunol. 159 (1997) 4139
98. Xue K., Rada C., and Neuberger M.S. The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2-/- ung-/- mice. J. Exp. Med. 203 (2006) 2085
99. Yan C.T., Boboila C., Souza E.K., Franco S., Hickernell T.R., Murphy M., Gumaste S., Geyer M., Zarrin A.A., Manis J.P., et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449 (2007) 478
100. Yelamos J., Klix N., Goyenechea B., Lozano F., Chui Y.L., Gonzalez Fernandez A., Pannell R., Neuberger M.S., and Milstein C. Targeting of non-Ig sequences in place of the V segment by somatic hypermutation. Nature 376 (1995) 225
101. Yoshikawa K., Okazaki I.M., Eto T., Kinoshita K., Muramatsu M., Nagaoka H., and Honjo T. AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296 (2002) 2033
102. Yu K., Chedin F., Hsieh C.L., Wilson T.E., and Lieber M.R. R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nat. Immunol. 4 (2003) 442
103. Yu K., Huang F.T., and Lieber M.R. DNA substrate length and surrounding sequence affect the activation-induced deaminase activity at cytidine. J. Biol. Chem. 279 (2004) 6496
104. Yurasov S., and Nussenzweig M.C. Regulation of autoreactive antibodies. Curr. Opin. Rheumatol. 19 (2007) 421
105. Yurasov S., Wardemann H., Hammersen J., Tsuiji M., Meffre E., Pascual V., and Nussenzweig M.C. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J. Exp. Med. 201 (2005) 703
106. Zarrin A.A., Alt F.W., Chaudhuri J., Stokes N., Kaushal D., Du Pasquier L., and Tian M. An evolutionarily conserved target motif for immunoglobulin class-switch recombination. Nat. Immunol. 5 (2004) 1275
107. Zarrin A.A., Del Vecchio C., Tseng E., Gleason M., Zarin P., Tian M., and Alt F.W. Antibody class switching mediated by yeast endonuclease-generated DNA breaks. Science 315 (2007) 377
108. Zarrin A.A., Goff P.H., Senger K., and Alt F.W. Sgamma3 switch sequences function in place of endogenous Sgamma1 to mediate antibody class switching. J. Exp. Med. 205 (2008) 1567
109. Zarrin A.A., Tian M., Wang J., Borjeson T., and Alt F.W. Influence of switch region length on immunoglobulin class switch recombination. Proc. Natl. Acad. Sci. USA 102 (2005) 2466
110. Zhang J., Bottaro A., Li S., Stewart V., and Alt F.W. A selective defect in IgG2b switching as a result of targeted mutation of the I gamma 2b promoter and exon. EMBO J. 12 (1993) 3529
111. Zhao Y., Pan-Hammarstrom Q., Yu S., Wertz N., Zhang X., Li N., Butler J.E., and Hammarstrom L. Identification of IgF, a hinge-region-containing Ig class, and IgD in Xenopus tropicalis. Proc. Natl. Acad. Sci. USA 103 (2006) 12087