Skip to main content
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1993 Feb 11;21(3):365–372. doi: 10.1093/nar/21.3.365

DNA sequences at immunoglobulin switch region recombination sites.

W Dunnick 1, G Z Hertz 1, L Scappino 1, C Gritzmacher 1
PMCID: PMC309126  PMID: 8441648

Abstract

The immunoglobulin heavy chain switch from synthesis of IgM to IgG, IgA or IgE is mediated by a DNA recombination event. Recombination occurs within switch regions, 2-10 kb segments of DNA that lie upstream of heavy chain constant region genes. A compilation of DNA sequences at more than 150 recombination sites within heavy chain switch regions is presented. Switch recombination does not appear to occur by homologous recombination. An extensive search for a recognition motif failed to find such a sequence, implying that switch recombination is not a site-specific event. A model for switch recombination that involves illegitimate priming of one switch region on another, followed by error-prone DNA synthesis, is proposed.

Full text

PDF
365

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Calame K., Kim S., Lalley P., Hill R., Davis M., Hood L. Molecular cloning of translocations involving chromosome 15 and the immunoglobulin C alpha gene from chromosome 12 in two murine plasmacytomas. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6994–6998. doi: 10.1073/pnas.79.22.6994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Davis D. D., Yoshida K., Kingsbury L., Sakano H. Circular DNA resulting from recombination between V-(D)-J joining signals and switch repetitive sequences in mouse thymocytes. J Exp Med. 1991 Mar 1;173(3):743–746. doi: 10.1084/jem.173.3.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Davis M. M., Kim S. K., Hood L. E. DNA sequences mediating class switching in alpha-immunoglobulins. Science. 1980 Sep 19;209(4463):1360–1365. doi: 10.1126/science.6774415. [DOI] [PubMed] [Google Scholar]
  4. DePinho R., Kruger K., Andrews N., Lutzker S., Baltimore D., Alt F. W. Molecular basis of heavy-chain class switching and switch region deletion in an Abelson virus-transformed cell line. Mol Cell Biol. 1984 Dec;4(12):2905–2910. doi: 10.1128/mcb.4.12.2905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dunnick W., Rabbitts T. H., Milstein C. An immunoglobulin deletion mutant with implications for the heavy-chain switch and RNA splicing. Nature. 1980 Aug 14;286(5774):669–675. doi: 10.1038/286669a0. [DOI] [PubMed] [Google Scholar]
  6. Dunnick W., Shell B. E., Dery C. DNA sequences near the site of reciprocal recombination between a c-myc oncogene and an immunoglobulin switch region. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7269–7273. doi: 10.1073/pnas.80.23.7269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dunnick W., Stavnezer J. Copy choice mechanism of immunoglobulin heavy-chain switch recombination. Mol Cell Biol. 1990 Jan;10(1):397–400. doi: 10.1128/mcb.10.1.397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dunnick W., Wilson M., Stavnezer J. Mutations, duplication, and deletion of recombined switch regions suggest a role for DNA replication in the immunoglobulin heavy-chain switch. Mol Cell Biol. 1989 May;9(5):1850–1856. doi: 10.1128/mcb.9.5.1850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eckhardt L. A., Birshtein B. K. Independent immunoglobulin class-switch events occurring in a single myeloma cell line. Mol Cell Biol. 1985 Apr;5(4):856–868. doi: 10.1128/mcb.5.4.856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Elenich L. A., Dunnick W. A. Sequence at insertion site of E.Tn retrotransposon into an immunoglobulin switch region suggests a role for switch recombinase. Nucleic Acids Res. 1991 Jan 25;19(2):396–396. doi: 10.1093/nar/19.2.396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Esser C., Radbruch A. Immunoglobulin class switching: molecular and cellular analysis. Annu Rev Immunol. 1990;8:717–735. doi: 10.1146/annurev.iy.08.040190.003441. [DOI] [PubMed] [Google Scholar]
  12. Fahrlander P. D., Sümegi J., Yang J. Q., Wiener F., Marcu K. B., Klein G. Activation of the c-myc oncogene by the immunoglobulin heavy-chain gene enhancer after multiple switch region-mediated chromosome rearrangements in a murine plasmacytoma. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3746–3750. doi: 10.1073/pnas.82.11.3746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Feiss M., Fisher R. A., Crayton M. A., Egner C. Packaging of the bacteriophage lambda chromosome: effect of chromosome length. Virology. 1977 Mar;77(1):281–293. doi: 10.1016/0042-6822(77)90425-1. [DOI] [PubMed] [Google Scholar]
  14. Fish S., Zenowich E., Fleming M., Manser T. Molecular analysis of original antigenic sin. I. Clonal selection, somatic mutation, and isotype switching during a memory B cell response. J Exp Med. 1989 Oct 1;170(4):1191–1209. doi: 10.1084/jem.170.4.1191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. French D. L., Laskov R., Scharff M. D. The role of somatic hypermutation in the generation of antibody diversity. Science. 1989 Jun 9;244(4909):1152–1157. doi: 10.1126/science.2658060. [DOI] [PubMed] [Google Scholar]
  16. Gerondakis S., Cory S., Adams J. M. Translocation of the myc cellular oncogene to the immunoglobulin heavy chain locus in murine plasmacytomas is an imprecise reciprocal exchange. Cell. 1984 Apr;36(4):973–982. doi: 10.1016/0092-8674(84)90047-3. [DOI] [PubMed] [Google Scholar]
  17. Gerstein R. M., Frankel W. N., Hsieh C. L., Durdik J. M., Rath S., Coffin J. M., Nisonoff A., Selsing E. Isotype switching of an immunoglobulin heavy chain transgene occurs by DNA recombination between different chromosomes. Cell. 1990 Nov 2;63(3):537–548. doi: 10.1016/0092-8674(90)90450-s. [DOI] [PubMed] [Google Scholar]
  18. Greenberg R., Lang R. B., Diamond M. S., Marcu K. B. A switch region inversion contributes to the aberrant rearrangement of a mu immunoglobulin heavy chain gene in MPC-11 cells. Nucleic Acids Res. 1982 Dec 11;10(23):7751–7761. doi: 10.1093/nar/10.23.7751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gritzmacher C. A., Liu F. T. Expression of a recombinant murine IgE in transfected myeloma cells. J Immunol. 1987 Jan 1;138(1):324–329. [PubMed] [Google Scholar]
  20. Gritzmacher C. A. Molecular aspects of heavy-chain class switching. Crit Rev Immunol. 1989;9(3):173–200. [PubMed] [Google Scholar]
  21. Hertz G. Z., Hartzell G. W., 3rd, Stormo G. D. Identification of consensus patterns in unaligned DNA sequences known to be functionally related. Comput Appl Biosci. 1990 Apr;6(2):81–92. doi: 10.1093/bioinformatics/6.2.81. [DOI] [PubMed] [Google Scholar]
  22. Hummel M., Berry J. K., Dunnick W. Switch region content of hybridomas: the two spleen cell Igh loci tend to rearrange to the same isotype. J Immunol. 1987 May 15;138(10):3539–3548. [PubMed] [Google Scholar]
  23. Iwasato T., Arakawa H., Shimizu A., Honjo T., Yamagishi H. Biased distribution of recombination sites within S regions upon immunoglobulin class switch recombination induced by transforming growth factor beta and lipopolysaccharide. J Exp Med. 1992 Jun 1;175(6):1539–1546. doi: 10.1084/jem.175.6.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Iwasato T., Shimizu A., Honjo T., Yamagishi H. Circular DNA is excised by immunoglobulin class switch recombination. Cell. 1990 Jul 13;62(1):143–149. doi: 10.1016/0092-8674(90)90248-d. [DOI] [PubMed] [Google Scholar]
  25. Jäck H. M., McDowell M., Steinberg C. M., Wabl M. Looping out and deletion mechanism for the immunoglobulin heavy-chain class switch. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1581–1585. doi: 10.1073/pnas.85.5.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kataoka T., Kawakami T., Takahashi N., Honjo T. Rearrangement of immunoglobulin gamma 1-chain gene and mechanism for heavy-chain class switch. Proc Natl Acad Sci U S A. 1980 Feb;77(2):919–923. doi: 10.1073/pnas.77.2.919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kataoka T., Miyata T., Honjo T. Repetitive sequences in class-switch recombination regions of immunoglobulin heavy chain genes. Cell. 1981 Feb;23(2):357–368. doi: 10.1016/0092-8674(81)90131-8. [DOI] [PubMed] [Google Scholar]
  28. Katz A., Kahana C. Rearrangement between ornithine decarboxylase and the switch region of the gamma 1 immunoglobulin gene in alpha-difluoromethylornithine resistant mouse myeloma cells. EMBO J. 1989 Apr;8(4):1163–1167. doi: 10.1002/j.1460-2075.1989.tb03487.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kim S., Davis M., Sinn E., Patten P., Hood L. Antibody diversity: somatic hypermutation of rearranged VH genes. Cell. 1981 Dec;27(3 Pt 2):573–581. doi: 10.1016/0092-8674(81)90399-8. [DOI] [PubMed] [Google Scholar]
  30. Lang R. B., Stanton L. W., Marcu K. B. On immunoglobulin heavy chain gene switching: two gamma 2b genes are rearranged via switch sequences in MPC-11 cells but only one is expressed. Nucleic Acids Res. 1982 Jan 22;10(2):611–630. doi: 10.1093/nar/10.2.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Liu F. T., Bohn J. W., Ferry E. L., Yamamoto H., Molinaro C. A., Sherman L. A., Klinman N. R., Katz D. H. Monoclonal dinitrophenyl-specific murine IgE antibody: preparation, isolation, and characterization. J Immunol. 1980 Jun;124(6):2728–2737. [PubMed] [Google Scholar]
  32. Manser T. The intraclonal diversity and control of antibody isotype switch recombination. Int Immunol. 1990;2(9):893–902. doi: 10.1093/intimm/2.9.893. [DOI] [PubMed] [Google Scholar]
  33. Marcu K. B., Lang R. B., Stanton L. W., Harris L. J. A model for the molecular requirements of immunoglobulin heavy chain class switching. Nature. 1982 Jul 1;298(5869):87–89. doi: 10.1038/298087a0. [DOI] [PubMed] [Google Scholar]
  34. Matsuoka M., Yoshida K., Maeda T., Usuda S., Sakano H. Switch circular DNA formed in cytokine-treated mouse splenocytes: evidence for intramolecular DNA deletion in immunoglobulin class switching. Cell. 1990 Jul 13;62(1):135–142. doi: 10.1016/0092-8674(90)90247-c. [DOI] [PubMed] [Google Scholar]
  35. Mills F. C., Brooker J. S., Camerini-Otero R. D. Sequences of human immunoglobulin switch regions: implications for recombination and transcription. Nucleic Acids Res. 1990 Dec 25;18(24):7305–7316. doi: 10.1093/nar/18.24.7305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mills F. C., Thyphronitis G., Finkelman F. D., Max E. E. Ig mu-epsilon isotype switch in IL-4-treated human B lymphoblastoid cells. Evidence for a sequential switch. J Immunol. 1992 Aug 1;149(3):1075–1085. [PubMed] [Google Scholar]
  37. Mowatt M. R., Dunnick W. A. DNA sequence of the murine gamma 1 switch segment reveals novel structural elements. J Immunol. 1986 Apr 1;136(7):2674–2683. [PubMed] [Google Scholar]
  38. Neuberger M. S., Calabi F. Reciprocal chromosome translocation between c-myc and immunoglobulin gamma 2b genes. Nature. 1983 Sep 15;305(5931):240–243. doi: 10.1038/305240a0. [DOI] [PubMed] [Google Scholar]
  39. Nikaido T., Yamawaki-Kataoka Y., Honjo T. Nucleotide sequences of switch regions of immunoglobulin C epsilon and C gamma genes and their comparison. J Biol Chem. 1982 Jul 10;257(13):7322–7329. [PubMed] [Google Scholar]
  40. Obata M., Kataoka T., Nakai S., Yamagishi H., Takahashi N., Yamawaki-Kataoka Y., Nikaido T., Shimizu A., Honjo T. Structure of a rearranged gamma 1 chain gene and its implication to immunoglobulin class-switch mechanism. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2437–2441. doi: 10.1073/pnas.78.4.2437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Ott D. E., Marcu K. B. Molecular requirements for immunoglobulin heavy chain constant region gene switch-recombination revealed with switch-substrate retroviruses. Int Immunol. 1989;1(6):582–591. doi: 10.1093/intimm/1.6.582. [DOI] [PubMed] [Google Scholar]
  42. Owens J. D., Jr, Finkelman F. D., Mountz J. D., Mushinski J. F. Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion. Mol Cell Biol. 1991 Nov;11(11):5660–5670. doi: 10.1128/mcb.11.11.5660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Petrini J., Dunnick W. A. Products and implied mechanism of H chain switch recombination. J Immunol. 1989 Apr 15;142(8):2932–2935. [PubMed] [Google Scholar]
  44. Petrini J., Shell B., Hummel M., Dunnick W. The immunoglobulin heavy chain switch: structural features of gamma 1 recombinant switch regions. J Immunol. 1987 Mar 15;138(6):1940–1946. [PubMed] [Google Scholar]
  45. Rudolph A. K., Burrows P. D., Wabl M. R. Thirteen hybridomas secreting hapten-specific immunoglobulin E from mice with Iga or Igb heavy chain haplotype. Eur J Immunol. 1981 Jun;11(6):527–529. doi: 10.1002/eji.1830110617. [DOI] [PubMed] [Google Scholar]
  46. Sakano H., Maki R., Kurosawa Y., Roeder W., Tonegawa S. Two types of somatic recombination are necessary for the generation of complete immunoglobulin heavy-chain genes. Nature. 1980 Aug 14;286(5774):676–683. doi: 10.1038/286676a0. [DOI] [PubMed] [Google Scholar]
  47. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Scappino L. A., Chu C., Gritzmacher C. A. Extended nucleotide sequence of the switch region of the murine gene encoding immunoglobulin E. Gene. 1991 Mar 15;99(2):295–296. doi: 10.1016/0378-1119(91)90142-x. [DOI] [PubMed] [Google Scholar]
  49. Schneider T. D., Stormo G. D., Gold L., Ehrenfeucht A. Information content of binding sites on nucleotide sequences. J Mol Biol. 1986 Apr 5;188(3):415–431. doi: 10.1016/0022-2836(86)90165-8. [DOI] [PubMed] [Google Scholar]
  50. Schultz C., Petrini J., Collins J., Claflin J. L., Denis K. A., Gearhart P., Gritzmacher C., Manser T., Shulman M., Dunnick W. Patterns and extent of isotype-specificity in the murine H chain switch DNA rearrangement. J Immunol. 1990 Jan 1;144(1):363–370. [PubMed] [Google Scholar]
  51. Shan H., Shlomchik M., Weigert M. Heavy-chain class switch does not terminate somatic mutation. J Exp Med. 1990 Aug 1;172(2):531–536. doi: 10.1084/jem.172.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Shapira S. K., Jabara H. H., Thienes C. P., Ahern D. J., Vercelli D., Gould H. J., Geha R. S. Deletional switch recombination occurs in interleukin-4-induced isotype switching to IgE expression by human B cells. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7528–7532. doi: 10.1073/pnas.88.17.7528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Shapira S. K., Vercelli D., Jabara H. H., Fu S. M., Geha R. S. Molecular analysis of the induction of immunoglobulin E synthesis in human B cells by interleukin 4 and engagement of CD40 antigen. J Exp Med. 1992 Jan 1;175(1):289–292. doi: 10.1084/jem.175.1.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Shell B. E., Collins J. T., Elenich L. A., Szurek P. F., Dunnick W. A. Two subfamilies of murine retrotransposon ETn sequences. Gene. 1990 Feb 14;86(2):269–274. doi: 10.1016/0378-1119(90)90289-4. [DOI] [PubMed] [Google Scholar]
  55. Siekevitz M., Kocks C., Rajewsky K., Dildrop R. Analysis of somatic mutation and class switching in naive and memory B cells generating adoptive primary and secondary responses. Cell. 1987 Mar 13;48(5):757–770. doi: 10.1016/0092-8674(87)90073-0. [DOI] [PubMed] [Google Scholar]
  56. Stanton L. W., Marcu K. B. Nucleotide sequence and properties of the murine gamma 3 immunoglobulin heavy chain gene switch region: implications for successive C gamma gene switching. Nucleic Acids Res. 1982 Oct 11;10(19):5993–6006. doi: 10.1093/nar/10.19.5993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Stanton L. W., Watt R., Marcu K. B. Translocation, breakage and truncated transcripts of c-myc oncogene in murine plasmacytomas. Nature. 1983 Jun 2;303(5916):401–406. doi: 10.1038/303401a0. [DOI] [PubMed] [Google Scholar]
  58. Stanton L. W., Yang J. Q., Eckhardt L. A., Harris L. J., Birshtein B. K., Marcu K. B. Products of a reciprocal chromosome translocation involving the c-myc gene in a murine plasmacytoma. Proc Natl Acad Sci U S A. 1984 Feb;81(3):829–833. doi: 10.1073/pnas.81.3.829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Szurek P., Petrini J., 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. 1985 Jul;135(1):620–626. [PubMed] [Google Scholar]
  60. Wuerffel R., Jamieson C. E., Morgan L., Merkulov G. V., Sen R., Kenter A. L. Switch recombination breakpoints are strictly correlated with DNA recognition motifs for immunoglobulin S gamma 3 DNA-binding proteins. J Exp Med. 1992 Aug 1;176(2):339–349. doi: 10.1084/jem.176.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Yancopoulos G. D., DePinho R. A., Zimmerman K. A., Lutzker S. G., Rosenberg N., Alt F. W. Secondary genomic rearrangement events in pre-B cells: VHDJH replacement by a LINE-1 sequence and directed class switching. EMBO J. 1986 Dec 1;5(12):3259–3266. doi: 10.1002/j.1460-2075.1986.tb04637.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Yoshida K., Matsuoka M., Usuda S., Mori A., Ishizaka K., Sakano H. Immunoglobulin switch circular DNA in the mouse infected with Nippostrongylus brasiliensis: evidence for successive class switching from mu to epsilon via gamma 1. Proc Natl Acad Sci U S A. 1990 Oct;87(20):7829–7833. doi: 10.1073/pnas.87.20.7829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. von Schwedler U., Jäck H. M., Wabl M. Circular DNA is a product of the immunoglobulin class switch rearrangement. Nature. 1990 May 31;345(6274):452–456. doi: 10.1038/345452a0. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES