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What role for AID: mutator, or assembler of the immunoglobulin mutasome?

Nature Immunology volume 4, pages 631–638 (2003)Cite this article

Abstract

Activation-induced cytidine deaminase (AID) has been shown to trigger three mechanisms for diversifying immunoglobulin genes—somatic hypermutation, isotype switch recombination and gene conversion—most probably by initiating cytidine deamination at the immunoglobulin locus. Although this deamination process has been shown to be potentially mutagenic by itself, most of the mutations generated in the physiological hypermutation process seem to be created through the AID-mediated assembly of a mutasome complex involving specific repair activities and error-prone DNA polymerases.

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Figure 1: Mutagenic and nonmutagenic repair of cytidine deamination in DNA.
Figure 2: Immunoglobulin gene hypermutation requires the assembly of an AID-targeted mutation complex.

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References

  1. Hesslein, D.G. & Schatz, D.G. Factors and forces controlling V(D)J recombination. Adv. Immunol. 78, 169–232 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Berek, C. & Milstein, C. The dynamic nature of the antibody repertoire. Immunol. Rev. 105, 5–26 (1988).

    Article  CAS  PubMed  Google Scholar 

  3. Stavnezer, J. Antibody class switching. Adv. Immunol. 61, 79–146 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Weill, J.-C. & Reynaud, C.-A. Rearrangement/hypermutation/gene conversion: when, where and why? Immunol. Today 17, 92–97 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Revy, P. et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102, 565–575 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Harris, R.S., Sale, J.E., Petersen-Mahrt, S.K. & Neuberger, M.S. AID is essential for immunoglobulin V gene conversion in a cultured B cell line. Curr. Biol. 12, 435–438 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Arakawa, H., Hauschild, J. & Buerstedde, J.M. Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion. Science 295, 1301–1306 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Yoshikawa, K. et al. AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296, 2033–2036 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Okazaki, I.M., Kinoshita, K., Muramatsu, M., Yoshikawa, K. & Honjo, T. The AID enzyme induces class switch recombination in fibroblasts. Nature 416, 340–345 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Gearhart, P. & Wood, R.D. Emerging links between hypermutation of antibody genes and DNA polymerases. Nat. Rev. Immunol. 1, 187–192 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Martin, A. & Scharff, M.D. AID and mismatch repair in antibody diversification. Nat. Rev. Immunol. 2, 605–614 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Papavasiliou, F.N. & Schatz, D.G. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell 109, S35–44 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Honjo, T., Kinoshita, K. & Muramatsu, M. Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu. Rev. Immunol. 20, 165–196 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Manis, J.P., Tian, M. & Alt, F.W. Mechanism and control of class-switch recombination. Trends Immunol. 23, 31–39 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Weill, J.-C. et al. Ig gene hypermutation: a mechanism is due. Adv. Immunol. 80, 183–202 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Muramatsu, M. et al. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol. Chem. 274, 18470–18476 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Anant, S. & Davidson, N.O. Molecular mechanisms of apolipoprotein B mRNA editing. Curr. Opin. Lipidol. 12, 159–165 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Wilson, M. et al. What limits affinity maturation of antibodies in Xenopus—the rate of somatic mutation or the ability to select mutants? EMBO J. 11, 4337–4719 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bachl, J. & Wabl, M. An immunoglobulin mutator that targets G.C base pairs. Proc. Natl. Acad. Sci. USA 93, 851–855 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rada, C., Ehrenstein, M.R., Neuberger, M.S. & Milstein, C. Hot-spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting. Immunity 9, 135–141 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Frey, S. et al. Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process. Immunity 9, 127–134 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Phung, Q.H. et al. Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein. J. Exp. Med. 187, 1745–1751 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jacobs, H. et al. Hypermutation of immunoglobulin genes in memory B cells of DNA repair-deficient mice. J. Exp. Med. 187, 1735–1743 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Denepoux, S. et al. Induction of somatic mutation in a human B cell line in vitro. Immunity 6, 35–46 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Sale, J.E. & Neuberger, M.S. TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. Immunity 9, 859–869 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Zan, H. et al. Induction of Ig somatic hypermutation and class switching in a human monoclonal IgM+IgD+ B cell line in vitro: definition of the requirements and modalities of hypermutation. J. Immunol. 162, 3437–3447 (1999).

    CAS  PubMed  Google Scholar 

  28. Martin, A. et al. Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 415, 802–806 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Di Noia, J. & Neuberger, M.S. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419, 43–48 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Rada, C. et al. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr. Biol. 12, 1748–1755 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Petersen-Mahrt, S.K., Harris, R.S. & Neuberger, M.S. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418, 99–103 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Harris, R.S., Petersen-Mahrt, S.K. & Neuberger, M.S. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Mol. Cell 10, 1247–1253 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Doi, T., Kinoshita, K., Ikegawa, M., Muramatsu, M. & Honjo, T. De novo protein synthesis is required for the activation-induced cytidine deaminase function in class-switch recombination. Proc. Natl. Acad. Sci. USA. 100, 2634–2638 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Krokan, H.E., Drablos, F. & Slupphaug, G. Uracil in DNA—occurrence, consequences and repair. Oncogene 21, 8935–8948 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Tissier, A., McDonald, J.P., Frank, E.G. & Woodgate, R. Pol ι, a remarkably error-prone human DNA polymerase. Genes Dev. 14, 1642–1650 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Matsuda, T. et al. Low fidelity DNA synthesis by human DNA polymerase-η. Nature 404, 1011–1013 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Kunkel, T.A., Pavlov, Y.I. & Bebenek, K. Functions of human DNA polymerases η, κ and ι suggested by their properties, including fidelity with undamaged DNA templates. DNA Repair 2, 135–149 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Johnson, R.E., Washington, M.T., Haracska, L., Prakash, S. & Prakash, L. Eukaryotic polymerases ι and ζ act sequentially to bypass DNA lesions. Nature 406, 1015–1019 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Bemark, M., Khamlichi, A.A., Davies, S.L. & Neuberger, M.S. Disruption of mouse polymerase ζ (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro. Curr. Biol. 10, 1213–1216 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Wittschieben, J. et al. Disruption of the developmentally regulated Rev3l gene causes embryonic lethality. Curr. Biol. 10, 1217–1220 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Esposito, G. et al. Disruption of the Rev3l-encoded catalytic subunit of polymerase ζ in mice results in early embryonic lethality. Curr. Biol. 10, 1221–1224 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Morrison, A. et al. REV3, a Saccharomyces cerevisiae gene whose function is required for induced mutagenesis, is predicted to encode a nonessential DNA polymerase. J. Bacteriol. 171, 5659–5667 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Masutani, C. et al. The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase η. Nature 399, 700–704 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Johnson, R.E., Kondratick, C.M., Prakash, S. & Prakash, L. hRAD30 mutations in the variant form of xeroderma pigmentosum. Science 285, 263–265 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Zeng, X. et al. DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat. Immunol. 2, 537–541 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Yavuz, S., Yavuz, A.S., Kraemer, K.H. & Lipsky, P.E. The role of polymerase η in somatic hypermutation determined by analysis of mutations in a patient with xeroderma pigmentosum variant. J. Immunol. 169, 3825–3830 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Faili, A. et al. AID-dependent somatic hypermutation occurs as a DNA single strand event in the BL2 cell line. Nat. Immunol. 3, 815–821 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Greagg, M.A. et al. A read-ahead function in archaeal DNA polymerases detects promutagenic template-strand uracil. Proc. Natl. Acad. Sci. USA 96, 9045–9050 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Faili, A. et al. Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase ι. Nature 419, 944–947 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Kannouche, P. et al. Localization of DNA polymerases η and ι to the replication machinery is tightly co-ordinated in human cells. EMBO J. 21, 6246–6256 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rogozin, I.B. & Kolchanov, N.A. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. Biochim. Biophys. Acta 1171, 11–18 (1992).

    Article  CAS  PubMed  Google Scholar 

  52. Rogozin, I.B., Pavlov, Y.I., Bebenek, K., Matsuda, T. & Kunkel, T.A. Somatic mutation hotspots correlate with DNA polymerase η error spectrum. Nat. Immunol. 2, 530–536 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Pavlov, Y.I. et al. Correlation of somatic hypermutation specificity and A-T base pair substitution errors by DNA polymerase η during copying of a mouse immunoglobulin κ light chain transgene. Proc. Natl. Acad. Sci. USA 99, 9954–9959 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zan, H. et al. The translesion DNA polymerase ζ plays a major role in Ig and Bcl-6 somatic hypermutation. Immunity 14, 643–653 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Diaz, M., Verkoczy, L.K., Flajnik, M.F. & Klinman, N.R. Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense RNA to DNA polymerase ζ. J. Immunol. 167, 327–335 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Reynaud, C.A. et al. Mismatch repair and immunoglobulin gene hypermutation: did we learn something? Immunol. Today 20, 522–527 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Alabyev, B. & Manser, T. Bcl-2 rescues the germinal center response but does not alter the V gene somatic hypermutation spectrum in MSH2-deficient mice. J. Immunol. 169, 3819–3824 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Wiesendanger, M., Kneitz, B., Edelmann, W. & Scharff, M.D. Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern. J. Exp. Med. 191, 579–584 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Phung, Q.H., Winter, D.B., Alrefai, R. & Gearhart, P.J. Hypermutation in Ig V genes from mice deficient in the MLH1 mismatch repair protein. J. Immunol. 162, 3121–3124 (1999).

    CAS  PubMed  Google Scholar 

  60. Winter, D.B. et al. Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2. Proc. Natl. Acad. Sci. USA 95, 6953–6958 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ehrenstein, M.R., Rada, C., Jones, A.M., Milstein, C. & Neuberger, M.S. Switch junction sequences in PMS2-deficient mice reveal a microhomology-mediated mechanism of Ig class switch recombination. Proc. Natl. Acad. Sci. USA 98, 14553–14558 (2002).

    Article  Google Scholar 

  62. Wang, H., Lawrence, C.W., Li, G.M. & Hays, J.B. Specific binding of human MSH2-MSH6 mismatch-repair protein heterodimers to DNA incorporating thymine- or uracil-containing UV light photoproducts opposite mismatched bases. J. Biol. Chem. 274, 16894–16900 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Edelmann, W. et al. Mutation in the mismatch repair gene Msh6 causes cancer susceptibility. Cell 91, 467–477 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Schlissel, M., Constantinescu, A., Morrow, T., Baxter, M. & Peng, A. Double-strand signal sequence breaks in V(D)J recombination are blunt, 5′-phosphorylated, RAG-dependent, and cell cycle regulated. Genes Dev. 7, 2520–2532 (1993).

    Article  CAS  PubMed  Google Scholar 

  65. Lin, W.C. & Desiderio, S. Cell cycle regulation of V(D)J recombination-activating protein RAG-2. Proc. Natl. Acad. Sci. USA 91, 2733–2737 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Petersen S. et al. AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching. Nature 414, 660–665 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Papavasiliou, F.N. & Schatz, D.G. Cell-cycle-regulated DNA double-stranded breaks in somatic hypermutation of immunoglobulin genes. Nature 408, 216–221 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Bross, L. et al. DNA double-strand breaks in immunoglobulin genes undergoing somatic hypermutation. Immunity 13, 589–597 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Bross, L., Muramatsu, M., Kinoshita, K., Honjo, T. & Jacobs, H. DNA double-strand breaks: prior to but not sufficient in targeting hypermutation. J. Exp. Med. 195, 1187–1192 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Papavasiliou, F.N. & Schatz, D.G. The activation-induced deaminase functions in a postcleavage step of the somatic hypermutation process. J. Exp. Med. 195, 1193–1198 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kong, Q. & Maizels, N. DNA breaks in hypermutating immunoglobulin genes: evidence for a break-and-repair pathway of somatic hypermutation. Genetics 158, 369–378 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Lebecque, S.G. & Gearhart, P.J. Boundaries of somatic mutation in rearranged immunoglobulin genes: 5′ boundary is near the promoter, and 3′ boundary is approximately 1 kb from V(D)J gene. J. Exp. Med. 172, 1717–1727 (1990).

    Article  CAS  PubMed  Google Scholar 

  73. Betz, A.G. et al. Elements regulating somatic hypermutation of an immunoglobulin gene: critical role for the intron enhancer/matrix attachment region. Cell 77, 239–248 (1994).

    Article  CAS  PubMed  Google Scholar 

  74. Peters, A. & Storb, U. Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 4, 57–65 (1996).

    Article  CAS  PubMed  Google Scholar 

  75. Goyenechea, B. et al. Cells strongly expressing Igκ transgenes show clonal recruitment of hypermutation: a role for both MAR and the enhancers. EMBO J. 16, 3987–3994 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fukita, Y., Jacobs, H. & Rajewsky, K. Somatic hypermutation in the heavy-chain locus correlates with transcription. Immunity 9, 105–114 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Bachl, J., Carlson, C., Gray-Schopfer, V., Dessing, M. & Olsson, C. Increased transcription levels induce higher mutation rates in a hypermutating cell line. J. Immunol. 166, 5051–5057 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Bransteitter, R., Pham, P., Scharff, M.D. & 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, 4102–4107 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chaudhuri, J. et al. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422, 726–730 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Ramiro, A.R., Stavropoulos, P., Jankovic, M. & Nussenzweig, M.C. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat Immunol. 4, 452–456 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Dörner, T., Foster, S.J., Brezinschek, H.-P. & Lipsky, P.E. Analysis of the targeting of the hypermutational machinery and the impact of subsequent selection on the distribution of nucleotides changes in human VHDHJ rearrangements. Immunol. Reviews 162, 161–171 (1998).

    Article  Google Scholar 

  82. Milstein, C., Neuberger, M.S. & Staden, R. Both DNA strands of antibody genes are hypermutation targets. Proc. Natl. Acad. Sci. USA 95, 8791–8794 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Spencer, J., Dunn, M. & Dunn-Walters, D.K. Characteristics of sequences around individual nucleotide substitutions in Ig VH genes suggest different GC and AT mutators. J. Immunol. 162, 6596–6601 (1999).

    CAS  PubMed  Google Scholar 

  84. Rada, C., Jarvis, J.M. & Milstein, C. AID-GFP chimeric protein increases hypermutation of Ig genes with no evidence of nuclear localization. Proc. Natl. Acad. Sci. USA 99, 7003–7008 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Martin, A. & Scharff, M.D. Somatic hypermutation of the AID transgene in B and non-B cells. Proc. Natl. Acad. Sci. USA 99, 12304–12308 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sale, J.E., Calandrini, D.M., Takata, M., Takeda, S. & Neuberger, M.S. Ablation of XRCC2/3 transforms immunoglobulin V-gene conversion into somatic hypermutation. Nature 412, 921–926 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Takata, M. et al. Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. Mol. Cell. Biol. 21, 2858–2866 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ehrenstein, M.R. & Neuberger, M.S. Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class-switch recombination: parallels with somatic hypermutation. EMBO J. 18, 3484–3490 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Schrader, C.E., Edelmann, W., Kucherlapati, R. & Stavnezer, J. Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes. J. Exp. Med. 190, 323–330 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Schrader, C.E., Vardo, J. & Stavnezer, J. Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions. J. Exp. Med. 195, 367–373 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lutzker, S., Rothman, P., Pollock, R., Coffman, R. & Alt, F.W. Mitogen- and IL-4-regulated expression of germline Igγ2b transcripts: evidence for directed heavy chain class switching. Cell 53, 177–184 (1988).

    Article  CAS  PubMed  Google Scholar 

  92. Stavnezer, J. et al. Immunoglobulin heavy-chain switching may be directed by prior induction of transcripts from constant-region genes. Proc. Natl. Acad. Sci. USA 85, 7704–7708 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hein, K. et al. Processing of switch transcripts is required for targeting of antibody class-switch recombination. J. Exp. Med. 188, 2369–2374 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Reaban, M.E. & Griffin, J.A. Induction of RNA-stabilized DNA conformers by transcription of an immunoglobulin switch region. Nature 348, 342–344 (1990).

    Article  CAS  PubMed  Google Scholar 

  95. Daniels, G.A. & Lieber, M.R. RNA:DNA complex formation upon transcription of immunoglobulin switch regions: implications for the mechanism and regulation of class switch recombination. Nucleic Acids Res. 23, 5006–5011 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shinkura, R. et al. The influence of transcriptional orientation on endogenous switch region function. Nat. Immunol. 4, 435–441 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Yu, K., Chedin, F., Hsieh, C.L., Wilson, T.E. & Lieber, M.R. R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nat. Immunol. 4, 442–451 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Kuppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B-cell lymphomas. Oncogene 20, 5580–5594 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Dunnick, W., Hertz, G.Z., Scappino, L. & Gritzmacher, C. DNA sequences at immunoglobulin switch region recombination sites. Nucleic Acids Res. 21, 365–372 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Nagaoka, H., Muramatsu, M., Yamamura, N., Kinoshita, K. & Honjo, T. Activation-induced deaminase (AID)-directed hypermutation in the immunoglobulin S region: implication of AID involvement in a common step of class switch recombination and somatic hypermutation. J. Exp. Med. 195 529–534 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Oppezzo, P. et al. Chronic lymphocytic leukemia B cells expressing AID display a dissociation between class switch recombination and somatic hypermutation. Blood 101, 4029–4032 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Pan-Hammarstrom, Q. et al. ATM is not required in somatic hypermutation of VH, but is involved in the introduction of mutations in switch μ region. J. Immunol. 170, 3707–3716 (2003).

    Article  PubMed  Google Scholar 

  103. Shen, H.M., Peters, A., Baron, B., Zhu, X. & Storb, U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280, 1750–1752 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Pasqualucci, L. et al. BCL-6 mutations in normal germinal-center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc. Natl. Acad. Sci. USA 95, 11816–11821 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Muschen, M. et al. Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal-center reaction. J. Exp. Med. 192, 1833–1840 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. McCarthy, H. et al. High expression of activation-induced cytidine deaminase (AID) and splice variants is a distinctive feature of poor prognosis chronic lymphocytic leukemia. Blood 101, 4903–4908 13 February 2003 (10.1182/blood-2002–09-2906).

    Article  CAS  PubMed  Google Scholar 

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  1. INSERM U373, Faculté de Médecine Necker–Enfants Malades, 156 rue de Vaugirard, Paris, 75730, Cedex 15, France

    Claude-Agnès Reynaud, Said Aoufouchi, Ahmad Faili & Jean-Claude Weill

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Reynaud, CA., Aoufouchi, S., Faili, A. et al. What role for AID: mutator, or assembler of the immunoglobulin mutasome?. Nat Immunol 4, 631–638 (2003). https://doi.org/10.1038/ni0703-631

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