Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting of somatic hypermutation

Nature Reviews Immunology volume 6, pages 573–583 (2006)Cite this article

Key Points

  • The targeting of somatic hypermutation (SHM) occurs at two distinct levels. 'Global' targeting refers to the fact that rearranged immunoglobulin variable regions are the primary substrate for SHM. By contrast, 'local' targeting refers to the observation that mutations are confined to a 1–2 kilobase (kb) region in the variable region.

  • SHM was once thought to target rearranged immunoglobulin variable regions exclusively. It has now been shown to occasionally mistarget oncogenes, including B-cell lymphoma 6 (BCL6) and CD95.

  • Activation-induced cytidine deaminase (AID) is required for SHM, but the substrate specificity of AID cannot explain the targeting of SHM.

  • DNA-repair processes are typically error-free but during SHM they are likely to be perturbed and rendered error-prone. The resulting error-prone repair pathway(s) must be targeted to rearranged immunoglobulin variable regions.

  • Studies using κ-light chain (Igκ)-like transgenes showed that immunoglobulin enhancer regions are required for targeting SHM to variable regions. More recently, however, studies of endogenous immunoglobulin loci have called into question both the role of immunoglobulin enhancers in SHM and the usefulness of traditional transgenes in dissecting the molecular mechanism of targeting.

  • Conventional histone modifications do not seem to have a direct role in targeting SHM. By contrast, the modification H2BSer14P (histone H2B phosphorylated on serine residue 14) is spatially and temporally correlated with SHM.

  • Recent insights and the development of new experimental strategies should continue to determine the mechanisms by which SHM is targeted to immunologlobulin loci, as well as the reason that this reaction is occasionally mistargeted to oncogenes.

Abstract

Somatic hypermutation (SHM) introduces mutations in the variable region of immunoglobulin genes at a rate of ∼10−3 mutations per base pair per cell division, which is 106-fold higher than the spontaneous mutation rate in somatic cells. To ensure genomic integrity, SHM needs to be targeted specifically to immunoglobulin genes. The rare mistargeting of SHM can result in mutations and translocations in oncogenes, and is thought to contribute to the development of B-cell malignancies. Despite years of intensive investigation, the mechanism of SHM targeting is still unclear. We review and attempt to reconcile the numerous and sometimes conflicting studies on the targeting of SHM to immunoglobulin loci, and highlight areas that hold promise for further investigation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Gene-specific targeting of somatic hypermutation.
Figure 2: Activation-induced-cytidine-deaminase-dependent lesion repair.
Figure 3: DNA lesions in somatic hypermutation and class switch recombination.
Figure 4: Recruitment of activation-induced cytidine deaminase by trans-acting factors.

Similar content being viewed by others

References

  1. Goossens, T., Klein, U. & Kuppers, R. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc. Natl Acad. Sci. USA 95, 2463–2468 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rogozin, I. B. & 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, 3382–3384 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Storb, U. et al. Cis-acting sequences that affect somatic hypermutation of Ig genes. Immunol. Rev. 162, 153–160 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. 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 

  6. Rada, C. & Milstein, C. The intrinsic hypermutability of antibody heavy and light chain genes decays exponentially. EMBO J. 20, 4570–4576 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Peters, A. & Storb, U. Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 4, 57–65 (1996). Duplication of the Igκ promoter immediately upstream of the Cκ region targeted SHM to this region in the context of an Igκ transgene. In light of this finding, a transcription-coupled model for SHM was first proposed.

    Article  CAS  PubMed  Google Scholar 

  8. Shen, H. M., Ratnam, S. & Storb, U. Targeting of the activation-induced cytosine deaminase is strongly influenced by the sequence and structure of the targeted DNA. Mol. Cell. Biol. 25, 10815–10821 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Longerich, S., Tanaka, A., Bozek, G., Nicolae, D. & Storb, U. The very 5′ end and the constant region of Ig genes are spared from somatic mutation because AID does not access these regions. J. Exp. Med. 202, 1443–1454 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. 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 

  12. 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 

  13. 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 

  14. Okazaki, I. M. et al. Constitutive expression of AID leads to tumorigenesis. J. Exp. Med. 197, 1173–1181 (2003). Transgenic mice designed to express AID ubiquitously develop T-cell lymphomas that have mutations in the genes encoding the T-cell receptor and MYC. Therefore, dysregulated expression of AID can lead to malignancy in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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 

  16. 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 

  17. Shinkura, R. et al. Separate domains of AID are required for somatic hypermutation and class-switch recombination. Nature Immunol. 5, 707–712 (2004).

    Article  CAS  Google Scholar 

  18. Ta, V. T. et al. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nature Immunol. 4, 843–848 (2003).

    Article  CAS  Google Scholar 

  19. Barreto, V., Reina- San-Martin, B., Ramiro, A. R., McBride, K. M. & Nussenzweig, M. C. C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion. Mol. Cell 12, 501–508 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Ito, S. et al. Activation-induced cytidine deaminase shuttles between nucleus and cytoplasm like apolipoprotein B mRNA editing catalytic polypeptide 1. Proc. Natl Acad. Sci. USA 101, 1975–1980 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brar, S. S., Watson, M. & Diaz, M. Activation-induced cytosine deaminase (AID) is actively exported out of the nucleus but retained by the induction of DNA breaks. J. Biol. Chem. 279, 26395–26401 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. McBride, K. M., Barreto, V., Ramiro, A. R., Stavropoulos, P. & Nussenzweig, M. C. Somatic hypermutation is limited by CRM1-dependent nuclear export of activation-induced deaminase. J. Exp. Med. 199, 1235–1244 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chaudhuri, J., Khuong, C. & Alt, F. W. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430, 992–998 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Pasqualucci, L., Kitaura, Y., Gu, H. & Dalla-Favera, R. PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells. Proc. Natl Acad. Sci. USA 103, 395–400 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Basu, U. et al. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 438, 508–511 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. Chaudhuri, J. et al. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422, 726–730 (2003). This elegant study shows that transcription can target AID activity to dsDNA by generating the ssDNA substrate preferred by this enzyme, providing a mechanistic link between transcription and SHM.

    Article  CAS  PubMed  Google Scholar 

  28. Pham, P., Bransteitter, R., Petruska, J. & Goodman, M. F. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 424, 103–107 (2003). This group shows that AID targets WRC motifs in ssDNA, introduces multiple mutations in one molecule of DNA (and thereby seems to function processively), and prefers to act on the non-transcribed strand of DNA that is exposed during transcription. Together, these findings provide a biochemical basis for several key features of SHM.

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  30. Dickerson, S. K., Market, E., Besmer, E. & Papavasiliou, F. N. AID mediates hypermutation by deaminating single stranded DNA. J. Exp. Med. 197, 1291–1296 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yu, K., Huang, F. T. & Lieber, M. R. DNA substrate length and surrounding sequence affect the activation-induced deaminase activity at cytidine. J. Biol. Chem. 279, 6496–6500 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. 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. Nature Immunol. 4, 452–456 (2003).

    Article  CAS  Google Scholar 

  33. Sohail, A., Klapacz, J., Samaranayake, M., Ullah, A. & Bhagwat, A. S. Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations. Nucleic Acids Res. 31, 2990–2994 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shen, H. M. & Storb, U. Activation-induced cytidine deaminase (AID) can target both DNA strands when the DNA is supercoiled. Proc. Natl Acad. Sci. USA 101, 12997–13002 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Neuberger, M. S., Harris, R. S., Di Noia, J. & Petersen-Mahrt, S. K. Immunity through DNA deamination. Trends Biochem. Sci. 28, 305–312 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Wilson, T. M. et al. MSH2–MSH6 stimulates DNA polymerase η, suggesting a role for A:T mutations in antibody genes. J. Exp. Med. 201, 637–645 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Reynaud, C. A., Aoufouchi, S., Faili, A. & Weill, J. C. What role for AID: mutator, or assembler of the immunoglobulin mutasome? Nature Immunol. 4, 631–638 (2003).

    Article  CAS  Google Scholar 

  39. Larson, E. D., Cummings, W. J., Bednarski, D. W. & Maizels, N. MRE11/RAD50 cleaves DNA in the AID/UNG-dependent pathway of immunoglobulin gene diversification. Mol. Cell 20, 367–375 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. 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 

  41. Cattoretti, G. et al. Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells. Blood 107, 3967–3975 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Longerich, S., Basu, U., Alt, F. & Storb, U. AID in somatic hypermutation and class switch recombination. Curr. Opin. Immunol. 18, 164–174 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Chaudhuri, J. & Alt, F. W. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nature Rev. Immunol. 4, 541–552 (2004).

    Article  CAS  Google Scholar 

  44. 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 

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

    Article  CAS  PubMed  Google Scholar 

  46. 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 

  47. 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 

  48. Zan, H., Wu, X., Komori, A., Holloman, W. K. & Casali, P. AID-dependent generation of resected double-strand DNA breaks and recruitment of Rad52/Rad51 in somatic hypermutation. Immunity 18, 727–738 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Haber, J. E. Hypermutation: give us a break. Nature Immunol. 2, 902–903 (2001).

    Article  CAS  Google Scholar 

  50. 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 

  51. Redon, C. et al. Histone H2A variants H2AX and H2AZ. Curr. Opin. Genet. Dev. 12, 162–169 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Reina-San-Martin, B. et al. H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation. J. Exp. Med. 197, 1767–1778 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Odegard, V. H., Kim, S. T., Anderson, S. M., Shlomchik, M. J. & Schatz, D. G. Histone modifications associated with somatic hypermutation. Immunity 23, 101–110 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Woo, C. J., Martin, A. & Scharff, M. D. Induction of somatic hypermutation is associated with modifications in immunoglobulin variable region chromatin. Immunity 19, 479–489 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Rada, C., Di Noia, J. M. & 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, 163–171 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. 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 

  57. Schrader, C. E., Linehan, E. K., Mochegova, S. N., Woodland, R. T. & Stavnezer, J. Inducible DNA breaks in Ig S regions are dependent on AID and UNG. J. Exp. Med. 202, 561–568 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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 

  59. 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). This paper marks the first time that a gene other than the immunoglobulin genes was shown to be a target of SHM in normal B cells.

    Article  CAS  PubMed  Google Scholar 

  60. 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 

  61. Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001). Multiple proto-oncogenes were found to contain SHM-like mutations in diffuse large B-cell lymphomas, pinpointing a possible origin for genomic instability during certain types of B-cell tumorigenesis.

    Article  CAS  PubMed  Google Scholar 

  62. Gordon, M. S., Kanegai, C. M., Doerr, J. R. & Wall, R. Somatic hypermutation of the B cell receptor genes B29 (Igβ, CD79b) and mb1 (Igα, CD79a). Proc. Natl Acad. Sci. USA 100, 4126–4131 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Muto, T. et al. Negative regulation of activation-induced cytidine deaminase in B cells. Proc. Natl Acad. Sci. USA 103, 2752–2757 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hori, M., Qi, C. F., Torrey, T. A., Huppi, K. & Morse, H. C. . The Bcl6 locus is not mutated in mouse B-cell lineage lymphomas. Leuk. Res. 26, 739–743 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Neuberger, M. S. et al. Monitoring and interpreting the intrinsic features of somatic hypermutation. Immunol. Rev. 162, 107–116 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Ramiro, A. R. et al. Role of genomic instability and p53 in AID-induced c-myc–Igh translocations. Nature 440, 105–109 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Ramiro, A. R. et al. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118, 431–438 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Franco, S. et al. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell 21, 201–214 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Shen, H. M., Michael, N., Kim, N. & Storb, U. The TATA binding protein, c-Myc and survivin genes are not somatically hypermutated, while Ig and BCL6 genes are hypermutated in human memory B cells. Int. Immunol. 12, 1085–1093 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. 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 

  71. O'Brien, R. L., Brinster, R. L. & Storb, U. Somatic hypermutation of an immunoglobulin transgene in κ transgenic mice. Nature 326, 405–409 (1987).

    Article  CAS  PubMed  Google Scholar 

  72. Sharpe, M. J., Milstein, C., Jarvis, J. M. & Neuberger, M. S. Somatic hypermutation of immunoglobulin κ may depend on sequences 3′ of Cκ and occurs on passenger transgenes. EMBO J. 10, 2139–2145 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Klotz, E. L. & Storb, U. Somatic hypermutation of a λ 2 transgene under the control of the λ enhancer or the heavy chain intron enhancer. J. Immunol. 157, 4458–4463 (1996).

    CAS  PubMed  Google Scholar 

  74. Kong, Q., Zhao, L., Subbaiah, S. & Maizels, N. A λ 3′ enhancer drives active and untemplated somatic hypermutation of a λ 1 transgene. J. Immunol. 161, 294–301 (1998).

    CAS  PubMed  Google Scholar 

  75. Giusti, A. M. & Manser, T. Hypermutation is observed only in antibody H chain V region transgenes that have recombined with endogenous immunoglobulin H DNA: implications for the location of cis-acting elements required for somatic mutation. J. Exp. Med. 177, 797–809 (1993).

    Article  CAS  PubMed  Google Scholar 

  76. Tumas-Brundage, K. & Manser, T. The transcriptional promoter regulates hypermutation of the antibody heavy chain locus. J. Exp. Med. 185, 239–250 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hengstschlager, M., Williams, M. & Maizels, N. A λ 1 transgene under the control of a heavy chain promoter and enhancer does not undergo somatic hypermutation. Eur. J. Immunol. 24, 1649–1656 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Sohn, J., Gerstein, R. M., Hsieh, C. L., Lemer, M. & Selsing, E. Somatic hypermutation of an immunoglobulin μ heavy chain transgene. J. Exp. Med. 177, 493–504 (1993).

    Article  CAS  PubMed  Google Scholar 

  79. Yelamos, J. et al. Targeting of non-Ig sequences in place of the V segment by somatic hypermutation. Nature 376, 225–229 (1995). This group shows that the rearranged variable region is not required for targeting SHM to an Igκ transgene. This study initiated the search for cis -acting elements that target SHM in transgenic mice.

    Article  CAS  PubMed  Google Scholar 

  80. Michael, N. et al. Effects of sequence and structure on the hypermutability of immunoglobulin genes. Immunity 16, 123–134 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Betz, A. G. et al. Elements regulating somatic hypermutation of an immunoglobulin κ gene: critical role for the intron enhancer/matrix attachment region. Cell 77, 239–248 (1994). This pivotal study shows that the Igκ intronic enhancer is required for targeting SHM to an Igκ transgene and that this activity is separate from the enhancer's role in transcription. In addition, the Igκ 3′ enhancer is also required for SHM of the transgene, but this function is most probably due to this enhancer's role in stimulating transcription. Together, these data lead to a model in which the SHM machinery is specifically recruited by immunoglobulin enhancers to immunoglobulin loci.

    Article  CAS  PubMed  Google Scholar 

  82. Queen, C. & Stafford, J. Fine mapping of an immunoglobulin gene activator. Mol. Cell. Biol. 4, 1042–1049 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Meyer, K. B. & Neuberger, M. S. The immunoglobulin κ locus contains a second, stronger B-cell-specific enhancer which is located downstream of the constant region. EMBO J. 8, 1959–1964 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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 

  85. Klix, N. et al. Multiple sequences from downstream of the Jκ cluster can combine to recruit somatic hypermutation to a heterologous, upstream mutation domain. Eur. J. Immunol. 28, 317–326 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Jolly, C. J. & Neuberger, M. S. Somatic hypermutation of immunoglobulin κ transgenes: association of mutability with demethylation. Immunol. Cell. Biol. 79, 18–22 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Michael, N. et al. The E box motif CAGGTG enhances somatic hypermutation without enhancing transcription. Immunity 19, 235–242 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Gorman, J. R. et al. The Igκ enhancer influences the ratio of Igκ versus Igλ B lymphocytes. Immunity 5, 241–252 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. van der Stoep, N., Gorman, J. R. & Alt, F. W. Reevaluation of 3′Eκ function in stage- and lineage-specific rearrangement and somatic hypermutation. Immunity 8, 743–750 (1998). Using mice lacking the Igκ 3′ enhancer, this study shows that the Igκ 3′ enhancer is not essential for transcription or mutation of the endogenous Igκ locus; these results are different from those obtained from Igκ transgenes.

    Article  CAS  PubMed  Google Scholar 

  90. Inlay, M. A. et al. Roles of the immunoglobulin κ light chain intronic and 3′ enhancers in Igk somatic hypermutation. J. Immunol. 177, 1146–1151 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Ronai, D., Iglesias-Ussel, M. D., Fan, M., Shulman, M. J. & Scharff, M. D. Complex regulation of somatic hypermutation by cis-acting sequences in the endogenous IgH gene in hybridoma cells. Proc. Natl Acad. Sci. USA 102, 11829–11834 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Perlot, T., Alt, F. W., Bassing, C. H., Suh, H. & Pinaud, E. Elucidation of IgH intronic enhancer functions via germ-line deletion. Proc. Natl Acad. Sci. USA 102, 14362–14367 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tumas-Brundage, K. M., Vora, K. A. & Manser, T. Evaluation of the role of the 3′α heavy chain enhancer [3′α E(hs1, 2)] in Vh gene somatic hypermutation. Mol. Immunol. 34, 367–378 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Liu, Z. M. et al. Chromatin structural analyses of the mouse Igκ gene locus reveal new hypersensitive sites specifying a transcriptional silencer and enhancer. J. Biol. Chem. 277, 32640–32649 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Schlissel, M. S. Regulation of activation and recombination of the murine Igκ locus. Immunol. Rev. 200, 215–223 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Staudt, L. M. & Lenardo, M. J. Immunoglobulin gene transcription. Annu. Rev. Immunol. 9, 373–398 (1991).

    Article  CAS  PubMed  Google Scholar 

  97. Henderson, A. & Calame, K. Transcriptional regulation during B cell development. Annu. Rev. Immunol. 16, 163–200 (1998).

    Article  CAS  PubMed  Google Scholar 

  98. Henderson, A. J. & Calame, K. L. Lessons in transcriptional regulation learned from studies on immunoglobulin genes. Crit. Rev. Eukaryot. Gene Expr. 5, 255–280 (1995).

    Article  CAS  PubMed  Google Scholar 

  99. Bain, G. & Murre, C. The role of E-proteins in B- and T-lymphocyte development. Semin. Immunol. 10, 143–153 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Kotani, A. et al. A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression. Proc. Nat. Acad. Sci. USA 102, 4506–4511 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Conlon, T. M. & Meyer, K. B. The chicken Ig light chain 3′-enhancer is essential for gene expression and regulates gene conversion via the transcription factor E2A. Eur. J. Immunol. 36, 139–148 (2006).

    Article  PubMed  Google Scholar 

  102. Kurdistani, S. K. & Grunstein, M. Histone acetylation and deacetylation in yeast. Nature Rev. Mol. Cell Biol. 4, 276–284 (2003).

    Article  CAS  Google Scholar 

  103. Nambu, Y. et al. Transcription-coupled events associating with immunoglobulin switch region chromatin. Science 302, 2137–2140 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Li, Z., Luo, Z. & Scharff, M. D. Differential regulation of histone acetylation and generation of mutations in switch regions is associated with Ig class switching. Proc. Natl Acad. Sci. USA 101, 15428–15433 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kuo, M. H., vom Baur, E., Struhl, K. & Allis, C. D. Gcn4 activator targets Gcn5 histone acetyltransferase to specific promoters independently of transcription. Mol. Cell 6, 1309–1320 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Liang, G. et al. Distinct localization of histone H3 acetylation and H3–K4 methylation to the transcription start sites in the human genome. Proc. Natl Acad. Sci. USA 101, 7357–7362 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cheung, W. L. et al. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 113, 507–517 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Ahn, S. H. et al. Sterile 20 kinase phosphorylates histone H2B at serine 10 during hydrogen peroxide-induced apoptosis in S. cerevisiae. Cell 120, 25–36 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Fernandez-Capetillo, O., Allis, C. D. & Nussenzweig, A. Phosphorylation of histone H2B at DNA double-strand breaks. J. Exp. Med. 199, 1671–1677 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Downs, J. A. et al. Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. Mol. Cell 16, 979–990 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Downs, J. A., Lowndes, N. F. & Jackson, S. P. A role for Saccharomyces cerevisiae histone H2A in DNA repair. Nature 408, 1001–1004 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Wang, C. L., Harper, R. A. & Wabl, M. Genome-wide somatic hypermutation. Proc. Natl Acad. Sci. USA 101, 7352–7356 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Parsa, J. Y. et al. AID mutates a non-immunoglobulin transgene independent of chromosomal position. Mol. Immunol. 14 March 2006 (doi:10.1016/j.molimm.2006.02.003).

  114. Dorner, T. et al. Analysis of the frequency and pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes. J. Immunol. 158, 2779–2789 (1997).

    CAS  PubMed  Google Scholar 

  115. Delpy, L., Sirac, C., Le Morvan, C. & Cogne, M. Transcription-dependent somatic hypermutation occurs at similar levels on functional and nonfunctional rearranged IgH alleles. J. Immunol. 173, 1842–1848 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Dunn-Walters, D. K., Dogan, A., Boursier, L., MacDonald, C. M. & Spencer, J. Base-specific sequences that bias somatic hypermutation deduced by analysis of out-of-frame human IgVH genes. J. Immunol. 160, 2360–2364 (1998).

    CAS  PubMed  Google Scholar 

  117. Kosak, S. T. et al. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296, 158–162 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Spilianakis, C. G., Lalioti, M. D., Town, T., Lee, G. R. & Flavell, R. A. Interchromosomal associations between alternatively expressed loci. Nature 435, 637–645 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Johnston, J. M. et al. Analysis of hypermutation in immunoglobulin heavy chain passenger transgenes. Eur. J. Immunol. 26, 1058–1062 (1996).

    Article  CAS  PubMed  Google Scholar 

  120. Terauchi, A. et al. A pivotal role for DNase I-sensitive regions 3b and/or 4 in the induction of somatic hypermutation of IgH genes. J. Immunol. 167, 811–820 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Morvan, C. L. et al. The immunoglobulin heavy-chain locus hs3b and hs4 3′ enhancers are dispensable for VDJ assembly and somatic hypermutation. Blood 102, 1421–1427 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. VaxInnate Corporation, 300 George Street, Suite 311, New Haven, 06511, Connecticut, USA

    Valerie H. Odegard

  2. Yale Medical School, Section of Immunobiology, 300 Cedar Street, Box 208011, New Haven, 06520-8011, Connecticut, USA

    David G. Schatz

Authors
  1. Valerie H. Odegard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David G. Schatz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David G. Schatz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

V(D)J recombination

Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, which leads to repertoire diversity of both T-cell and B-cell receptors.

Transition mutations

Base changes in DNA in which a pyrimidine (cytidine (C) or thymidine (T)) is replaced by another pyrimidine, or a purine (adenosine (A) or guanosine (G)) is replaced by another purine.

Transversion mutations

Base changes in DNA in which a pyrimidine (cytidine (C) or thymidine (T)) is replaced by a purine (adenosine (A) or guanosine (G)), or a purine is replaced by a pyrimidine.

Hotspot motif

A short DNA motif (DGYW or WRCH; where D denotes adenosine (A), guanosine (G) or thymidine (T); Y denotes cytidine (C) or T; W denotes A or T; R denotes A or G; and H denotes T, C or A) in which mutations are preferentially inserted during somatic hypermutation.

Elongating transcription complex

A complex comprising the RNA polymerase and its associated proteins that is formed during the elongation phase of transcription.

Nuclear export signal

A highly conserved, leucine-rich sequence that facilitates protein trafficking from the nucleus to the cytoplasm.

Template supercoiling

Compaction of DNA by twisting and folding.

Abasic site

A site created by the loss of a purine or pyrimidine from DNA.

Base-excision repair

A DNA-repair pathway that removes single bases from DNA, such as uridine nucleotides arising by deamination of cytidine. Repair is initiated by a DNA glycosylase that is specialized for a particular class of damage.

Mismatch repair

A repair pathway that recognizes and corrects mismatched base pairs (typically those that arise from errors of chromosomal DNA replication).

Chromosomal translocation

An aberration of chromosome structure in which a portion of one chromosome is broken off and becomes attached to another.

Death domain

A protein–protein interaction domain found in many proteins that are involved in signalling and apoptosis.

Enhancer

A control element in DNA to which regulatory proteins bind and influence the rate of gene transcription. Enhancers function in an orientation- and position-independent manner (that is, they can function either upstream or downstream of the associated gene, or in an intron).

Matrix attachment region

DNA sites that are linked to the nuclear matrix. They are thought to have roles in gene regulation and higher order chromosome organization.

Octamer-binding transcription factor proteins

A family of transcription factors that recognize and bind a conserved eight nucleotide motif found in the regulatory regions of many genes, including immunoglobulin genes.

DT40 cells

A chicken B-cell line that undergoes high rates of homologous recombination and immunoglobulin gene conversion.

BL2 cell line

A human B-cell lymphoma cell line that can be stimulated to undergo SHM.

H3–K4 methylation

The addition of methyl groups to lysine residue 4 on histone H3.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Odegard, V., Schatz, D. Targeting of somatic hypermutation. Nat Rev Immunol 6, 573–583 (2006). https://doi.org/10.1038/nri1896

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1896

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing