Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Dec 5;92(25):11485–11489. doi: 10.1073/pnas.92.25.11485

Equine severe combined immunodeficiency: a defect in V(D)J recombination and DNA-dependent protein kinase activity.

R Wiler 1, R Leber 1, B B Moore 1, L F VanDyk 1, L E Perryman 1, K Meek 1
PMCID: PMC40426  PMID: 8524788

Abstract

V(D)J rearrangement is the molecular mechanism by which an almost infinite array of specific immune receptors are generated. Defects in this process result in profound immunodeficiency as is the case in the C.B-17 SCID mouse or in RAG-1 (recombination-activating gene 1) or RAG-2 deficient mice. It has recently become clear that the V(D)J recombinase most likely consists of both lymphoid-specific factors and ubiquitously expressed components of the DNA double-strand break repair pathway. The deficit in SCID mice is in a factor that is required for both of these pathways. In this report, we show that the factor defective in the autosomal recessive severe combined immunodeficiency of Arabian foals is required for (i) V(D)J recombination, (ii) resistance to ionizing radiation, and (iii) DNA-dependent protein kinase activity.

Full text

PDF
11485

Images in this article

11487Fig. 1
on p.11487
11487Fig. 2
on p.11487
11488Fig. 5
on p.11488

Selected References

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

  1. Biedermann K. A., Sun J. R., Giaccia A. J., Tosto L. M., Brown J. M. scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1394–1397. doi: 10.1073/pnas.88.4.1394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blunt T., Finnie N. J., Taccioli G. E., Smith G. C., Demengeot J., Gottlieb T. M., Mizuta R., Varghese A. J., Alt F. W., Jeggo P. A. Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell. 1995 Mar 10;80(5):813–823. doi: 10.1016/0092-8674(95)90360-7. [DOI] [PubMed] [Google Scholar]
  3. Bosma G. C., Custer R. P., Bosma M. J. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. doi: 10.1038/301527a0. [DOI] [PubMed] [Google Scholar]
  4. Carter T., Vancurová I., Sun I., Lou W., DeLeon S. A DNA-activated protein kinase from HeLa cell nuclei. Mol Cell Biol. 1990 Dec;10(12):6460–6471. doi: 10.1128/mcb.10.12.6460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dvir A., Peterson S. R., Knuth M. W., Lu H., Dynan W. S. Ku autoantigen is the regulatory component of a template-associated protein kinase that phosphorylates RNA polymerase II. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11920–11924. doi: 10.1073/pnas.89.24.11920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Felsburg P. J., Somberg R. L., Perryman L. E. Domestic animal models of severe combined immunodeficiency: canine X-linked severe combined immunodeficiency and severe combined immunodeficiency in horses. Immunodefic Rev. 1992;3(4):277–303. [PubMed] [Google Scholar]
  7. Finnie N. J., Gottlieb T. M., Blunt T., Jeggo P. A., Jackson S. P. DNA-dependent protein kinase activity is absent in xrs-6 cells: implications for site-specific recombination and DNA double-strand break repair. Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):320–324. doi: 10.1073/pnas.92.1.320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ford J. E., Home W. A., Gibson D. M. Light chain isotype regulation in the horse. Characterization of Ig kappa genes. J Immunol. 1994 Aug 1;153(3):1099–1111. [PubMed] [Google Scholar]
  9. Fulop G. M., Phillips R. A. The scid mutation in mice causes a general defect in DNA repair. Nature. 1990 Oct 4;347(6292):479–482. doi: 10.1038/347479a0. [DOI] [PubMed] [Google Scholar]
  10. Getts R. C., Stamato T. D. Absence of a Ku-like DNA end binding activity in the xrs double-strand DNA repair-deficient mutant. J Biol Chem. 1994 Jun 10;269(23):15981–15984. [PubMed] [Google Scholar]
  11. Gottlieb T. M., Jackson S. P. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell. 1993 Jan 15;72(1):131–142. doi: 10.1016/0092-8674(93)90057-w. [DOI] [PubMed] [Google Scholar]
  12. Hesse J. E., Lieber M. R., Gellert M., Mizuuchi K. Extrachromosomal DNA substrates in pre-B cells undergo inversion or deletion at immunoglobulin V-(D)-J joining signals. Cell. 1987 Jun 19;49(6):775–783. doi: 10.1016/0092-8674(87)90615-5. [DOI] [PubMed] [Google Scholar]
  13. Home W. A., Ford J. E., Gibson D. M. L chain isotype regulation in horse. I. Characterization of Ig lambda genes. J Immunol. 1992 Dec 15;149(12):3927–3936. [PubMed] [Google Scholar]
  14. Honjo T. Immunoglobulin genes. Annu Rev Immunol. 1983;1:499–528. doi: 10.1146/annurev.iy.01.040183.002435. [DOI] [PubMed] [Google Scholar]
  15. Jackson S. P., MacDonald J. J., Lees-Miller S., Tjian R. GC box binding induces phosphorylation of Sp1 by a DNA-dependent protein kinase. Cell. 1990 Oct 5;63(1):155–165. doi: 10.1016/0092-8674(90)90296-q. [DOI] [PubMed] [Google Scholar]
  16. Kienker L. J., Kuziel W. A., Tucker P. W. T cell receptor gamma and delta gene junctional sequences in SCID mice: excessive P nucleotide insertion. J Exp Med. 1991 Oct 1;174(4):769–773. doi: 10.1084/jem.174.4.769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kirchgessner C. U., Patil C. K., Evans J. W., Cuomo C. A., Fried L. M., Carter T., Oettinger M. A., Brown J. M. DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. Science. 1995 Feb 24;267(5201):1178–1183. doi: 10.1126/science.7855601. [DOI] [PubMed] [Google Scholar]
  18. Kotloff D. B., Bosma M. J., Ruetsch N. R. V(D)J recombination in peritoneal B cells of leaky scid mice. J Exp Med. 1993 Dec 1;178(6):1981–1994. doi: 10.1084/jem.178.6.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kuhn A., Gottlieb T. M., Jackson S. P., Grummt I. DNA-dependent protein kinase: a potent inhibitor of transcription by RNA polymerase I. Genes Dev. 1995 Jan 15;9(2):193–203. doi: 10.1101/gad.9.2.193. [DOI] [PubMed] [Google Scholar]
  20. Lees-Miller S. P., Chen Y. R., Anderson C. W. Human cells contain a DNA-activated protein kinase that phosphorylates simian virus 40 T antigen, mouse p53, and the human Ku autoantigen. Mol Cell Biol. 1990 Dec;10(12):6472–6481. doi: 10.1128/mcb.10.12.6472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lees-Miller S. P., Godbout R., Chan D. W., Weinfeld M., Day R. S., 3rd, Barron G. M., Allalunis-Turner J. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. Science. 1995 Feb 24;267(5201):1183–1185. doi: 10.1126/science.7855602. [DOI] [PubMed] [Google Scholar]
  22. Lewis S. M. The mechanism of V(D)J joining: lessons from molecular, immunological, and comparative analyses. Adv Immunol. 1994;56:27–150. doi: 10.1016/s0065-2776(08)60450-2. [DOI] [PubMed] [Google Scholar]
  23. Lieber M. R., Hesse J. E., Lewis S., Bosma G. C., Rosenberg N., Mizuuchi K., Bosma M. J., Gellert M. The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination. Cell. 1988 Oct 7;55(1):7–16. doi: 10.1016/0092-8674(88)90004-9. [DOI] [PubMed] [Google Scholar]
  24. Lunn D. P., McClure J. T., Schobert C. S., Holmes M. A. Abnormal patterns of equine leucocyte differentiation antigen expression in severe combined immunodeficiency foals suggests the phenotype of normal equine natural killer cells. Immunology. 1995 Mar;84(3):495–499. [PMC free article] [PubMed] [Google Scholar]
  25. Malynn B. A., Blackwell T. K., Fulop G. M., Rathbun G. A., Furley A. J., Ferrier P., Heinke L. B., Phillips R. A., Yancopoulos G. D., Alt F. W. The scid defect affects the final step of the immunoglobulin VDJ recombinase mechanism. Cell. 1988 Aug 12;54(4):453–460. doi: 10.1016/0092-8674(88)90066-9. [DOI] [PubMed] [Google Scholar]
  26. McGuire T. C., Poppie M. J. Hypogammaglobulinemia and thymic hypoplasia in horses: a primary combined immunodeficiency disorder. Infect Immun. 1973 Aug;8(2):272–277. doi: 10.1128/iai.8.2.272-277.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mimori T., Hardin J. A. Mechanism of interaction between Ku protein and DNA. J Biol Chem. 1986 Aug 5;261(22):10375–10379. [PubMed] [Google Scholar]
  28. Oettinger M. A., Schatz D. G., Gorka C., Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990 Jun 22;248(4962):1517–1523. doi: 10.1126/science.2360047. [DOI] [PubMed] [Google Scholar]
  29. Ono M., Tucker P. W., Capra J. D. Production and characterization of recombinant human Ku antigen. Nucleic Acids Res. 1994 Sep 25;22(19):3918–3924. doi: 10.1093/nar/22.19.3918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pergola F., Zdzienicka M. Z., Lieber M. R. V(D)J recombination in mammalian cell mutants defective in DNA double-strand break repair. Mol Cell Biol. 1993 Jun;13(6):3464–3471. doi: 10.1128/mcb.13.6.3464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Peterson S. R., Kurimasa A., Oshimura M., Dynan W. S., Bradbury E. M., Chen D. J. Loss of the catalytic subunit of the DNA-dependent protein kinase in DNA double-strand-break-repair mutant mammalian cells. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3171–3174. doi: 10.1073/pnas.92.8.3171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rathmell W. K., Chu G. A DNA end-binding factor involved in double-strand break repair and V(D)J recombination. Mol Cell Biol. 1994 Jul;14(7):4741–4748. doi: 10.1128/mcb.14.7.4741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rathmell W. K., Chu G. Involvement of the Ku autoantigen in the cellular response to DNA double-strand breaks. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7623–7627. doi: 10.1073/pnas.91.16.7623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Roth D. B., Menetski J. P., Nakajima P. B., Bosma M. J., Gellert M. V(D)J recombination: broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes. Cell. 1992 Sep 18;70(6):983–991. doi: 10.1016/0092-8674(92)90248-b. [DOI] [PubMed] [Google Scholar]
  35. Roth D. B., Nakajima P. B., Menetski J. P., Bosma M. J., Gellert M. V(D)J recombination in mouse thymocytes: double-strand breaks near T cell receptor delta rearrangement signals. Cell. 1992 Apr 3;69(1):41–53. doi: 10.1016/0092-8674(92)90117-u. [DOI] [PubMed] [Google Scholar]
  36. Roth D. B., Zhu C., Gellert M. Characterization of broken DNA molecules associated with V(D)J recombination. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10788–10792. doi: 10.1073/pnas.90.22.10788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Satoh M., Wang J., Reeves W. H. Role of free p70 (Ku) subunit in posttranslational stabilization of newly synthesized p80 during DNA-dependent protein kinase assembly. Eur J Cell Biol. 1995 Feb;66(2):127–135. [PubMed] [Google Scholar]
  38. Schatz D. G., Oettinger M. A., Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989 Dec 22;59(6):1035–1048. doi: 10.1016/0092-8674(89)90760-5. [DOI] [PubMed] [Google Scholar]
  39. Schuler W., Ruetsch N. R., Amsler M., Bosma M. J. Coding joint formation of endogenous T cell receptor genes in lymphoid cells from scid mice: unusual P-nucleotide additions in VJ-coding joints. Eur J Immunol. 1991 Mar;21(3):589–596. doi: 10.1002/eji.1830210309. [DOI] [PubMed] [Google Scholar]
  40. Schuler W., Weiler I. J., Schuler A., Phillips R. A., Rosenberg N., Mak T. W., Kearney J. F., Perry R. P., Bosma M. J. Rearrangement of antigen receptor genes is defective in mice with severe combined immune deficiency. Cell. 1986 Sep 26;46(7):963–972. doi: 10.1016/0092-8674(86)90695-1. [DOI] [PubMed] [Google Scholar]
  41. Smider V., Rathmell W. K., Lieber M. R., Chu G. Restoration of X-ray resistance and V(D)J recombination in mutant cells by Ku cDNA. Science. 1994 Oct 14;266(5183):288–291. doi: 10.1126/science.7939667. [DOI] [PubMed] [Google Scholar]
  42. Taccioli G. E., Gottlieb T. M., Blunt T., Priestley A., Demengeot J., Mizuta R., Lehmann A. R., Alt F. W., Jackson S. P., Jeggo P. A. Ku80: product of the XRCC5 gene and its role in DNA repair and V(D)J recombination. Science. 1994 Sep 2;265(5177):1442–1445. doi: 10.1126/science.8073286. [DOI] [PubMed] [Google Scholar]
  43. Taccioli G. E., Rathbun G., Oltz E., Stamato T., Jeggo P. A., Alt F. W. Impairment of V(D)J recombination in double-strand break repair mutants. Science. 1993 Apr 9;260(5105):207–210. doi: 10.1126/science.8469973. [DOI] [PubMed] [Google Scholar]
  44. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983 Apr 14;302(5909):575–581. doi: 10.1038/302575a0. [DOI] [PubMed] [Google Scholar]
  45. Tuteja N., Tuteja R., Ochem A., Taneja P., Huang N. W., Simoncsits A., Susic S., Rahman K., Marusic L., Chen J. Human DNA helicase II: a novel DNA unwinding enzyme identified as the Ku autoantigen. EMBO J. 1994 Oct 17;13(20):4991–5001. doi: 10.1002/j.1460-2075.1994.tb06826.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Zhu C., Roth D. B. Characterization of coding ends in thymocytes of scid mice: implications for the mechanism of V(D)J recombination. Immunity. 1995 Jan;2(1):101–112. doi: 10.1016/1074-7613(95)90082-9. [DOI] [PubMed] [Google Scholar]
  47. van Gent D. C., McBlane J. F., Ramsden D. A., Sadofsky M. J., Hesse J. E., Gellert M. Initiation of V(D)J recombination in a cell-free system. Cell. 1995 Jun 16;81(6):925–934. doi: 10.1016/0092-8674(95)90012-8. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES