Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity

Immunity

Volumn 9, Issue 3, 1998, Pages 355-366

  Taccioli, Guillermo E ^a   Amatucci, Aldo G ^a   Beamish, Heather J ^b   Gell, David ^c   Xiang, Xie H ^a   Torres Arzayus, Maria I ^a   Priestley, Ann ^b   Jackson, Stephen P ^c   Rothstein, Ann Marshak ^a   Jeggo, Penny A ^c   Herrera, Victoria L M ^a  

^a BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF SUSSEX   (United Kingdom)

^c UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; CD8 ANTIGEN; DNA; DNA BINDING PROTEIN; PROTEIN KINASE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; B LYMPHOCYTE; COMBINED IMMUNODEFICIENCY; CONTROLLED STUDY; EMBRYO; ENZYME ACTIVE SITE; ENZYME ACTIVITY; FIBROBLAST; GENE DISRUPTION; GENE TARGETING; GENETIC RECOMBINATION; IMMUNOBLOTTING; LYMPHOCYTE DIFFERENTIATION; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; RADIOSENSITIVITY; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SCID MOUSE; SOUTHERN BLOTTING; T LYMPHOCYTE; THYMOCYTE;

EID: 0032167545     PISSN: 10747613     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1074-7613(00)80618-4     Document Type: Article

References (74)

1. Anderson, C.W., and Carter, T.H. (1996). The DNA-activated protein kinase-DNA-PK. In Current Topics in Microbiology and Immunology, R. Jessberger and M.R. Lieber, eds. (Heidelberg: Springer-Verlag), pp. 91-111.
2. Araki, R., Fujimori, A., Hamatani, K., Mita, K., Saito, T., Mori, M., Fukumura, R., Morimyo, M., Muto, M., Itoh, M., et al. (1997). Non-sense mutation at Tyr-4046 in the DNA-dependent protein kinase catalytic subunit of severe combined immune deficiency mice. Proc. Natl. Acad. Sci. USA 94, 2438-2443.
3. Biedermann, K.A., Sun, J., Giaccia, A.J., Tosto, L.M., and Brown, J.M. (1991).scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair. Proc. Natl. Acad. Sci. USA 88, 1394-1397.
4. Blackwell, T.K., Malynn, B.A., Pollock, R.R., Ferrier, P., Covey, L.R., Fullop, G.M., Phillips, R.A., Yancopoulos, G.D., and Alt, F.W. (1989). Isolation of scid pre-B cells that rearrange kappa light chain genes: formation of normal signal and abnormal coding joints. EMBO J. 8, 735-742.
5. Blunt, T., Finnie, N.J., Taccioli, G.E., Smith, G.C.M., Demengeot, J., Gottlieb, T.M., Mizuta, R., Varghese, A.J., Alt, F.W., Jeggo, P.A., and Jackson, S.P. (1995). Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell 80, 813-823.
6. Blunt, T., Gell, D., Fox, M., Taccioli, G.E., Lehmann, A.R., Jackson, S.P., and Jeggo, P.A. (1996). Identification of a nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse. Proc. Natl. Acad. Sci. USA 93, 10285-10290.
7. Bogue, M.A., Zhu, C., Aguilar-Cordova, E., Donehover, L.A., and Roth, D.B. (1996). p53 is required for both radiation-induced differentiation and rescue of V(D)J rearrangements in scid mouse thymocytes. Genes Dev. 10, 553-565.
8. Bosma, M.J., and Carroll, A.M. (1991). The SCID mutant: definition, characterization, and potential uses. Annu. Rev. Immunol. 9, 323-350.
9. Boubnov, N.V., Hall, K.T., Wills, Z., Lee, S.E., He, D.M., Benjamin, D.M., Pulaski, C.R., Band, H., Reeves, W., Hendrickson, E.A., and Weaver, D.T. (1995). Complementation of the ionizing radiation sensitivity, DNA end binding and V(D)J recombination defects on double-strand break repair mutants by the p86 Ku autoantigen. Proc. Natl. Acad. Sci. USA 92, 890-894.
10. Carroll, A.M., and Bosma, M.J. (1991). T-lymphocye development in scid mice is arrested shortly after the initiation of T-call receptor δ gene recombination. Genes Dev. 5, 1357-1366.
11. Carroll, A.M., Slack, J.K., and Chang, W.-T. (1993a). Biased T-cell receptor δ element recombination in scid thymocytes. Mol. Cell. Biol. 13, 3632-3640.
12. Carroll, A.M., Slack, J.K., and Mu, X. (1993b). V(D)J recombination generates a high frequency of nonstandard TCR Dδ-associated rearrangemets in thymocytes. J. Immunol. 6, 2222-2230.
13. Carter, T., Vancurova, I., Sun, I., Lou, W., and DeLeon, S. (1990). A DNA-activated protein kinase from HeLa cell nuclei. Mol. Cel. Biol. 10, 6460-6471.
14. Chen, J., and Alt, F.W. (1994). Rag-2 Deficient Blastocyst Complementation (Academic Press).
15. Danska, J.S., Plumio, F., Williams, C.J., Huner, O., Dick, J.E., and Guidos, C.J. (1994). Rescue of T cell-specific V(D)J recombination in SCID mice by DNA-damaging agents. Science 266, 450-455.
16. Danska, J.S., Holland, D.P., Mariathasa, S., Williams, K.M., and Guidos. C.J. (1996). Biochemical and genetic defects in the DNA-dependent protein kinase in murine scid lymphocytes. Mol. Cell. Biol. 16, 5507-5517.
17. Errami, A., Smider, V., Rathmell, W.K., He, D.M., Hendrickson, E.A., Zdzienicka, M.Z., and Chu, G. (1996). Ku86 defines the genetic defect and restores X-ray resistance and V(D)J recombination to complementation group 5 hamster cell mutants. Mol. Cell. Biol. 16, 1519-1526.
18. Finnie, N.J., Gottlieb, T.M., Blunt, T., Jeggo, P.A., and Jackson, S.P. (1995). DNA-PK activity is absent in xrs-6 cells; implications for site-specific recombination and DNA double strand break repair. Proc. Natl. Acad. Sci. USA 92, 320-324.
19. Fullop, G.M., and Phillips, R.A. (1990). The scid mutation in mice causes a general defect in DNA repair. Nature 346, 479-482.
20. Gao, Y., Chaudhuri, J., Zhu, C., Davidson, L., Weaver, D.T., and Alt, F.W. (1998). A targed DNA-PKcs-null mutation reveals DNA-PK-independent functions for Ku in V(D)J recombination. Immunity 9, 367-376.
21. Getts, R.C., and Stamato, T.D. (1994). Absence of a Ku-like DNA end-binding activity in the xrs double-strand DNA repair deficient mutant. J. Biol. Chem. 269, 15981-15984.
22. Gu, Y., Seidl, K.J., Rathbun, G.A., Zhu, C., Manis, J.P., van der Stoep, N., Davidson, L., Cheng, H.-L., Sekiguchi, J.M., Frank, K., et al. (1997). Growth retardation and leaky SCID phenotype of Ku70-deficient Mice. Immunity 7, 653-665.
23. Guidos, C.J., Williams, C.J., Wu, G.E., Paige, C.J., and Danska, J.S. (1995). Development of CD4+CD8+ thymocytes in RAG-deficient mice through a T cell receptor β chain-independent pathway. J. Exp. Med. 181, 1187-1195.
24. Hammarsten, O., and Chu, G. (1998). DNA-dependent protein kinase: DNA binding and activation in the absence of Ku. Proc. Natl. Acad. Sci. USA. 95, 525-530.
25. Hartley, K.O., Gell, D., Smith, G.C.M., Zhang, H., Divecha, N., Connelly, M.A., Admon, A., Lees-Miller, S.P., Anderson, C.W., and Jackson, S.P. (1995). DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Cell 82, 849-856.
26. Hendrickson, E.A., Qin, X.-Q., Bump, E.A., Schatz, D.G., Oettinger, M.A., and Weaver, D.T. (1991). A link beween double-strand break-related repair and V(D)J recombination: the scid mutation. Proc. Natl. Acad. Sci. USA 88, 4061-4065.
27. Jeggo, P.A. (1997). DNA-PK: at the cross-roads of biochemistry and genetics. Mut. Res. 384, 1-14.
28. Jeggo, P.A., Taccioli, G.E., and Jackson, S.P. (1995). Menage atrois: double stranded break repair, V(D)J recombination and DNA-PK. BioEssay 17, 949-957.
29. Jhappan, C., Morse, H.C., Fleischmann, R.D., Gottesman, M.M., and Merlino, G. (1997). DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Nat. Genet. 17, 483-486.
30. Jiang, D., Lenardo, M.J., and Zuniga-Pflucker, J.C. (1996). p53 prevents maturation to the CD+CD8+ stage of thymocyte differentiation in the absence of T cell receptor rearrangements. J. Exp. Med. 183, 1923-1928.
31. Kirchgessner, C.U., Patil, C.K., Evans, J.W., Cuomo, C.A., Fried, L.M., Carter, T., Oettinger, M.A., and Brown, J.M. (1995). DNA-dependent kinase (p350) as a candidate gene for the murine scid defect. Science 267, 1178-1183.
32. Lees-Miller, S.P. (1996). The DNA-dependent protein kinase. DNA-PK: 10 years and no ends in sight. Biochem. Cell Biol. 74, 503-512.
33. Lewis, S.M. (1994). The mechanisms of V(D)J rejoining: lessons from molecular, immunological, and comparative analysis. Adv. Immunol. 56, 27-149.
34. Li, Z., Otevrel, T., Gao, Y., Hwei-Ling., C., Seed, B., Stamato, T.D., Taccioli, G.E., and Alt, F.W. (1995). The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination. Cell 83, 1079-1089.
35. Lieber, M.R., Hesse, J.E., Lewis, S., Bosma, G.C., Rosenberg, N., Mizuuchi, K., Bosma, M.J., and Gellert, M. (1988). The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination. Cell 55, 7-16.
36. Lin, J.Y.-D., Muhlmann-Diaz, M.C., Stackhouse, M.A., Robinson, J.F., Taccioli, G.E., Chen, D.J., and Bedford, J.S. (1997). An ionizing radiation-sensitive CHO mutant cell line: irs-20. IV. Genetic complementation, V(D)J recombination and the scid phenotype. Rad. Res. 147, 166-171.
37. Livak, F., Welsh, S.C., Guidos, C.J., Crispe, I.N., Dnaska, J.S., and Schatz, D.G. (1996). Transient restoration of gene rearrangement at multiple T cell receptor loci in γ-irradiated scid mice. J. Exp. Med. 184, 419-428.
38. Malynn, B.A., Blackwell, T.K., Fullop, G.M., Rathbun, G., Furley, A.J.W., Ferrier, P., Heinke, L.B., Phillips, R.A., Yancopoulos, G.D., and Alt, F.W. (1988). The scid defect affects the final step of the immunoglobin VDJ recombinase mechanism. Cell 54, 453-460.
39. Mizuta, R., Taccioli, G.E., and Alt, F.W. (1996). The V(D)J recombination defect in the xrs-6 cell line results from a point mutation in the Ku80 gene. Int. Immunol. 8, 1467-1471.
40. Mombaerts, P., Iacomini, J., Johnson, R.S., Herrup, K., Tonewaga, S., and Papaionnou, V.E. (1992). RAG-1 deficient mice have no mature B and T lymphocytes. Cell 68, 869-867.
41. Murphy, W.J., Durum, S.K., Anver, M.R., Ferris, O.K., McVicar, D.W., O'Shea, J.J., Ruscetti, S.K., Smith, M.R., Young, H.A., and Longo, D.L. (1994). Induction of T cell diferentiation and lymphomagenesis in the thymus of mice with severe combined immune deficiency (SCID). J. Immunol. 153, 1004-1014.
42. Nussenzweig, A., Chen, C., da Costa Soares, V., Sanchez, M., Sokol, K., Nussenzweig, M.C., and Li, G.C. (1996). Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Science 382, 551-555.
43. Nussenzweig, A., Sokol, K., Burgman, P., Li, L., and Li, G.C. (1997). Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects of ionizing radiation on growth, survival, and development. Proc. Natl. Acad. Sci. USA 94, 13588-13593.
44. Oettinger, M.A., Schatz, D.G., Gorka, C., and Baltimore, D. (1990). RAG 1 and RAG 2, adjacent genes that synergistically activate V(D)J recombination. Science 248, 1517-1523.
45. Ouyang, H., Nussenzweig, A., Kurimasa, A., da Costa Soares, V., Li, X., Cordon-Cardo, C., Li, W.-H., Cheong, N., Nussenzweig, M., Illiakis, G., Chen, D., and Li, G.C. (1997). Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo. J. Exp. Med. 186, 921-929.
46. Pergola, F., Zdzienicka, M.Z., and Lieber, M.R. (1993). V(D)J recombination in mammalian cell mutants defective in DNA double-strand break repair. Mol. Cell. Biol. 13, 3464-3471.
47. Peterson, S.R., Kurimasa, A., Osimura, M., Dynan, W.S., Bradbury, E.M., and Chen, D. (1995). Loss of the catalytic subunit of the DNA-dependent protein kinase in DNA double-strand-break-repair mutant mammalian cells. Proc. Natl. Acad. Sci. USA 87, 3450-3453.
48. Peterson, S.R., Stackhouse, M., Waltman, M.J., Chen, F., Sato, K., and Chen, D.J. (1997). Characterization of two DNA double-stranded break repair-deficient cell lines that express inactive DNA-dependent protein kinase catalytic subunits. J. Biol. Chem. 272, 10227-10231.
49. Petrini, J.H., Carroll, A.M., and Bosma, M.J. (1990). T cell receptor gene rearrangements in functional T cell clones from severe combined immunodeficient (scid) mice: reversion of the scid phenotype in individual lymphocytes progenitors. Proc. Natl. Acad. Sci. USA. 87, 3450-3453.
50. Poltoratsky, V.P., Shi, X., York, J.D., Lieber, M.R., and Carter, T.H. (1995). Human DNA-activated protein kinase (DNA-PK) is homologous to phosphatidylinosotol kinases. J. Immunol. 155, 4529-4533.
51. Priestley, A., Gell, D., Amatucci, A.G., Muhlmann-Diaz, M.C., Singleton, K., Beamish, H.J., Smith, G.C.M., Blunt, T., Schakwyk, L.C., Bedford, J.S., et al. (1998). Molecular and biochemical characterization of DNA dependent protein kinase in defective rodent mutants. Nucleic Acid Res. 26, 1965-1973.
52. Ramsden, D.A., van Gent, D., and Gellert, M. (1997). Specificity in V(D)J recombination: new lessons from biochemistry and genetics. Curr. Opin. Immunol. 9, 114-120.
53. Rathmell, W.K., and Chu, G. (1994). Involvement of the Ku autoantigen in the cellular response to the DNA double strand breaks. Proc. Natl. Acad. Sci. USA 91, 7623-7627.
54. Roth, D.B., Zhu, C., and Geller, M. (1993). Characterization of broken DNA molecules associated with V(D)J recombination. Proc. Natl. Acad. Sci. USA 90, 10788-10792.
55. Schatz, D.G., Oettinger, M.A., and Baltimore, D. (1989). The V(D)J recombination activating gene, RAG-1. Cell 59, 1035-1048.
56. Schlissel, M.S., and Baltimore, D. (1991). Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription. Cell 58, 1001-1007.
57. Schlissel, M.S., Corcoran, L.M., and Baltimore, D. (1991). Virus-transformed pre-B cells show ordered activation but not inactivation of immunoglobulin gene rearrangement and transcription. J. Exp. Med. 173, 711-720.
58. Schlissel, M., Constantinescu, A., Morrow, T., Baxter, M., and Peng, A. (1993). 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.
59. Schuler, W. (1990). The scid mouse mutant: biology and nature of the defect. In Molecular Biology of B Cell Developments. Cytokines, Volume 3, C. Sorg, ed. (Basel: S. Karger), pp. 132-153.
60. Shin, E.K., Perryman, L.E., and Meek, K. (1997). A kinase-negative mutation of DNA-PKcs in equine SCID results in defective coding and signal joint formation. J. Immunol. 158, 3565-3569.
61. Shinkai, Y., Rathbun, G., Lam, K., Oltz, E.M., Stewart, V., Mendelsohn, M., Charon, J., Datta, M., Young, F., Stall, A.M., and Alt, F.W. (1992). RAG-2 deficient mice lack mature lymphocytes due to inability to initiate VDJ rearrangement. Cell 68, 855-867.
62. Singleton, B.K., Priestley, A., Steingrimsdottir, H., Gell, D., Blunt, T., Jackson, S.P., Lehmann, A.R., and Jeggo, P.A. (1997). Molecular and biochemical characterization of xrs mutants defective in Ku80. Mol. Cell. Biol. 17, 1264-1273.
63. Smider, V., Rathmell, W.M., Lieber, M.R., and Chu, G. (1994). Restoration of X-ray resistance and V(D)J recombination in mutant cells by Ku cDNA. Science. 266, 288-291.
64. Taccioli, G.E., and Alt, F.W. (1995). Potential targets for autosomal SCID mutations. Curr. Opin. Immunol. 7, 436-440.
65. Taccioli, G.E., Rathbun, G., Shinkai, Y., Oltz, E., Cheng, H.-L., Whitmore, G., Stamato, T., Jeggo, P.A., and Alt, F.W. (1992). Activities involved in V(D)J recombination. Curr. Top. Microbiol. Immunol. 182, 107-113.
66. Taccioli, G.E., Rathbun, G., Oltz, E., Stamato, T., Jeggo, P.A., and Alt, F.W. (1993). Impairment Of V(D)J recombination in double-strand break repair mutants. Science 260, 207-210.
67. Taccioli, G.E., Cheng, H-L., Varghese, A.J., Whitmore, G.F., and Alt, F.W. (1994a). A DNA repair defect in Chinese hamster ovary cell affects V(D)J recombination similarly to the murine scid mutation. J. Biol. Chem. 269, 7439-7442.
68. Taccioli, G.E., Gottlieb, T.M., Blunt, T., Priestley, A., Demengeot, J., Mizuta, R., Lehmann, A.R., Alt, F.W, Jackson, S.P., and Jeggo, P.A. (1994b). Ku80 is the product of the XRCC5 gene: a direct link with DNA repair and V(D)J recombination. Science 265, 1442-1445.
69. Tonegawa, S. (1993). Somatic generation of antibody diversity. Nature 302, 575-581.
70. Willerford, D.M., Swat, W., and Alt, F.W. (1996). Developmental regulation of V(D)J recombination and lymphocyte differentiation. Curr. Opin. Genet. Dev. 6, 603-609.
71. Yaneva, M., Kowalewski, T., and Lieber, M.R. (1997). Interaction of DNA-dependent protein kinase with DNA and with Ku: biochemical and atomic-force microscopy studies. EMBO J. 16, 5098-5112.
72. Zhu, C., Bogue, M.A., Lim, D.-S., Hasty, P., and Roth, D.B. (1996a). Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates. Cell 86, 379-389.
73. Zhu, C., Bogue, M.A., and Roth, D.B. (1996b).Thymocyte differentiation in γ-irradiated severe-combined immunodeficient mice: characterization of intermediates and products of V(D)J recombination at the T cell receptor a locus. Eur. J. Immunol. 26, 2859-2865.
74. Zuniga-Pflucker, J.C., Jiang, D., Schwartzberg, P.L., and Lenardo, M.J. (1994). Sublethal γ-radiation induces differentiation of CD4-/ CD8-into CD4+/CD8+ thymocytes without T cell receptor β rearrangements in recombinase activation gene 2 -/-Mice. J. Exp. Med. 180, 1517-1521.