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Gene Review

Prkdc  -  protein kinase, DNA activated, catalytic...

Mus musculus

Synonyms: AI326420, AU019811, DNA-PK, DNA-PK catalytic subunit, DNA-PKcs, ...
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Disease relevance of Prkdc


Psychiatry related information on Prkdc

  • However, SCID-bg mice always showed the smallest within-group variance (individual difference) in the serum guinea pig IgG concentrations (P < 0.05, versus C.B.-17-scid-AGM1 mice at 1, 2, and 3 weeks and versus C.B.-17-scid mice at 2 weeks) [5].

High impact information on Prkdc

  • Mice homozygous for the scid mutation (scid mice) are severely deficient in functional B and T lymphocytes [6].
  • Thus, scid mice are of interest for studies of both normal and abnormal lymphocyte development and function [6].
  • Multiple organs of the human hematolymphoid system have been successfully engrafted into the immunodeficient C.B-17 scid scid mouse, including fetal liver, thymus, lymph node, and skin [7].
  • ISS-ODN and bacterial DNA activate DNA-PK, which in turn contributes to activation of IKK and NF-kappaB [8].
  • Herein, we demonstrate that administration of bacterial DNA and ISS-ODN to mice lacking the catalytic subunit of DNA-PK (DNA-PKcs) and in vitro stimulation of BMDM from these mice result in defective induction of IL-6 and IL-12 [8].

Chemical compound and disease context of Prkdc


Biological context of Prkdc

  • This has been confirmed by finding BALB/c-specific functional polymorphism in Prkdc, a gene on mouse chromosome 16 that encodes the catalytic subunit of DNA-dependent protein kinase [14].
  • Differences in mammary tumor occurrence among genotypes for Prkdc and Cdkn2a in N2 mice were not statistically significant [15].
  • In the crosses (C.S-R1 x BALB/c)F(1) x 129/SvJ and (C.S-R1 x BALB/c)F(1) x C.B17, enhanced apoptosis occurred in the absence of the wild-type allele at Prkdc [16].
  • Two variations T6,418C and G11,530A, which induce amino acid substitutions C2,140R downstream from the putative leucine zipper motif and V3,844M near the kinase domain, respectively, were found between BALB/c and STS for Prkdc [16].
  • Because mice with combined disruptions of ATM and other NHEJ components (ligase IV, Artemis) are viable, our data suggest a novel NHEJ-independent function for Prkdc/Ku that is required to complete early embryogenesis in the absence of ATM [3].

Anatomical context of Prkdc

  • DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus [1].
  • These unanticipated features of the Ku70-deficient phenotype with respect to lymphocyte development and V(D)J recombination may reflect differential functions of the three DNA-PK components [17].
  • Finally, while DNA-PK-null fibroblasts exhibited increased IR sensitivity, DNA-PKcs-deficient ES cells did not [18].
  • By 1 yr of age, approximately 60% of BALB-gld and 30% of C3H-gld mice had monoclonal B cell populations that grew and metastasized in scid recipients but in most cases were rejected by immunocompetent mice [19].
  • Interestingly, none of the tumors showed changes in the genomic organization of c-Myc but many had one or more somatically-acquired MuLV proviral integrations that were transmitted in scid passages and cell lines [19].

Associations of Prkdc with chemical compounds


Physical interactions of Prkdc

  • DNA-PK interacts with p53 but may also have p53-independent functions [24].
  • DNA-dependent protein kinase (DNA-PK) is a DNA repair enzyme composed of a DNA-binding component called Ku70/80 and a catalytic subunit called DNA-PKcs [25].
  • Here we demonstrate that c-Abl interacts constitutively with DNA-PK [26].
  • We found that a large fraction of CD4+ T cells from inflamed colonic LP and from non-inflamed PC, mLN and S expressed high levels of P- and E-selectin-binding epitopes (P-Lhi) in transplanted scid mice, but not in congenic, immunocompetent control mice [13].

Enzymatic interactions of Prkdc

  • DNAPK is normally activated by DNA dsbs and phosphorylates the p53 protein [23].
  • In vitro evidence indicates that DNA-dependent protein kinase (DNA-PK) can also phosphorylate and thus potentially activate Abl kinase activity in response to IR exposure [27].
  • Although purified DNA-PK could phosphorylate a peptide derived from Akt that contains amino acid Ser-473, it could not phosphorylate full-length Akt2 [28].

Regulatory relationships of Prkdc


Other interactions of Prkdc

  • These results suggest that exposure to ionizing radiation facilitates a partial bypass of the scid defect, perhaps by inducing p53-dependent DNA damage response pathways [29].
  • The DNA-dependent protein kinase is a mammalian protein complex composed of Ku70, Ku80, and DNA-PKcs subunits that has been implicated in DNA double-strand break repair and V(D)J recombination [33].
  • Therefore, we conclude that DNA-PKcs has Artemis-independent functions in CSR and normal development [34].
  • The lack of a neuronal death phenotype in DNA-PKcs-deficient embryos and the milder phenotype of Ku-deficient versus XRCC4- or Lig4-deficient embryos correlate with relative leakiness of residual end joining in these mutant backgrounds as assayed by a V(D)J recombination end joining assay [35].
  • Genetic interaction between DNA polymerase beta and DNA-PKcs in embryogenesis and neurogenesis [36].

Analytical, diagnostic and therapeutic context of Prkdc

  • Here, by gene targeting, we have constructed a mouse with a disruption in the kinase domain of DNA-PKcs, generating an animal model completely devoid of DNA-PK activity [33].
  • Xenospecific cytotoxic T cells were also capable of mediating tumor rejection when adoptively transferred into scid/scid mice bearing established human COLO 205 xenografts [37].
  • No DP thymocytes were detected in thymocytes of adoptive transfer experiments in scid mice that were derived from p53(-/-)Bcl11b(-/-) precursors but ISP thymocytes increased in the proportion and in the cell number approximately three times higher than those from Bcl11b(-/-) precursors [38].
  • Remarkably, in vivo treatment of scid mice challenged with an invariably fatal number of Ramos-BT cells with B43-Gen at a dose level < 1/10 the maximum tolerated dose resulted in 70% long-term event-free survival [39].
  • In vitro, L. donovani was unable to trigger IFN-gamma production from scid spleen cell cultures under conditions which allowed efficient triggering by bacterial stimuli [40].


  1. DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Jhappan, C., Morse, H.C., Fleischmann, R.D., Gottesman, M.M., Merlino, G. Nat. Genet. (1997) [Pubmed]
  2. Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene. Yu, Y., Okayasu, R., Weil, M.M., Silver, A., McCarthy, M., Zabriskie, R., Long, S., Cox, R., Ullrich, R.L. Cancer Res. (2001) [Pubmed]
  3. p53-Independent apoptosis disrupts early organogenesis in embryos lacking both ataxia-telangiectasia mutated and Prkdc. Gladdy, R.A., Nutter, L.M., Kunath, T., Danska, J.S., Guidos, C.J. Mol. Cancer Res. (2006) [Pubmed]
  4. Catalytic subunit of DNA-dependent protein kinase: impact on lymphocyte development and tumorigenesis. Kurimasa, A., Ouyang, H., Dong, L.J., Wang, S., Li, X., Cordon-Cardo, C., Chen, D.J., Li, G.C. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  5. SCID-bg mice as xenograft recipients. Shibata, S., Asano, T., Ogura, A., Hashimoto, N., Hayakawa, J., Uetsuka, K., Nakayama, H., Doi, K. Lab. Anim. (1997) [Pubmed]
  6. The SCID mouse mutant: definition, characterization, and potential uses. Bosma, M.J., Carroll, A.M. Annu. Rev. Immunol. (1991) [Pubmed]
  7. The SCID-hu mouse: a small animal model for HIV infection and pathogenesis. McCune, J., Kaneshima, H., Krowka, J., Namikawa, R., Outzen, H., Peault, B., Rabin, L., Shih, C.C., Yee, E., Lieberman, M. Annu. Rev. Immunol. (1991) [Pubmed]
  8. DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA. Chu, W., Gong, X., Li, Z., Takabayashi, K., Ouyang, H., Chen, Y., Lois, A., Chen, D.J., Li, G.C., Karin, M., Raz, E. Cell (2000) [Pubmed]
  9. Preterm delivery induced by LPS in syngeneically impregnated BALB/c and NOD/SCID mice. Lin, Y., Xie, M., Chen, Y., Di, J., Zeng, Y. J. Reprod. Immunol. (2006) [Pubmed]
  10. DNA double-strand breaks, p53, and apoptosis during lymphomagenesis in scid/scid mice. Gurley, K.E., Vo, K., Kemp, C.J. Cancer Res. (1998) [Pubmed]
  11. Silibinin up-regulates DNA-protein kinase-dependent p53 activation to enhance UVB-induced apoptosis in mouse epithelial JB6 cells. Dhanalakshmi, S., Agarwal, C., Singh, R.P., Agarwal, R. J. Biol. Chem. (2005) [Pubmed]
  12. Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo. Graham, C., Tucker, C., Creech, J., Favours, E., Billups, C.A., Liu, T., Fouladi, M., Freeman, B.B., Stewart, C.F., Houghton, P.J. Clin. Cancer Res. (2006) [Pubmed]
  13. Expression of selectin-binding epitopes and cytokines by CD4+ T cells repopulating scid mice with colitis. Thoma, S., Bonhagen, K., Vestweber, D., Hamann, A., Reimann, J. Eur. J. Immunol. (1998) [Pubmed]
  14. Adenoma multiplicity in irradiated Apc(Min) mice is modified by chromosome 16 segments from BALB/c. Degg, N.L., Weil, M.M., Edwards, A., Haines, J., Coster, M., Moody, J., Ellender, M., Cox, R., Silver, A. Cancer Res. (2003) [Pubmed]
  15. BALB/c alleles for Prkdc and Cdkn2a interact to modify tumor susceptibility in Trp53+/- mice. Blackburn, A.C., Brown, J.S., Naber, S.P., Otis, C.N., Wood, J.T., Jerry, D.J. Cancer Res. (2003) [Pubmed]
  16. Variations in Prkdc encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and susceptibility to radiation-induced apoptosis and lymphomagenesis. Mori, N., Matsumoto, Y., Okumoto, M., Suzuki, N., Yamate, J. Oncogene (2001) [Pubmed]
  17. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. 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., Stanhope-Baker, P., Schlissel, M.S., Roth, D.B., Alt, F.W. Immunity (1997) [Pubmed]
  18. A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Gao, Y., Chaudhuri, J., Zhu, C., Davidson, L., Weaver, D.T., Alt, F.W. Immunity (1998) [Pubmed]
  19. Spontaneous development of plasmacytoid tumors in mice with defective Fas-Fas ligand interactions. Davidson, W.F., Giese, T., Fredrickson, T.N. J. Exp. Med. (1998) [Pubmed]
  20. ATM and the catalytic subunit of DNA-dependent protein kinase activate NF-kappaB through a common MEK/extracellular signal-regulated kinase/p90(rsk) signaling pathway in response to distinct forms of DNA damage. Panta, G.R., Kaur, S., Cavin, L.G., Cortés, M.L., Mercurio, F., Lothstein, L., Sweatman, T.W., Israel, M., Arsura, M. Mol. Cell. Biol. (2004) [Pubmed]
  21. Regulation of the pancreatic duodenal homeobox-1 protein by DNA-dependent protein kinase. Lebrun, P., Montminy, M.R., Van Obberghen, E. J. Biol. Chem. (2005) [Pubmed]
  22. Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit. Jin, S., Kharbanda, S., Mayer, B., Kufe, D., Weaver, D.T. J. Biol. Chem. (1997) [Pubmed]
  23. p53 induction, cell cycle checkpoints, and apoptosis in DNAPK-deficient scid mice. Gurley, K.E., Kemp, C.J. Carcinogenesis (1996) [Pubmed]
  24. p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase. Fedier, A., Moawad, A., Haller, U., Fink, D. Int. J. Oncol. (2003) [Pubmed]
  25. Role of DNA-dependent protein kinase in neuronal survival. Chechlacz, M., Vemuri, M.C., Naegele, J.R. J. Neurochem. (2001) [Pubmed]
  26. Functional interaction between DNA-PK and c-Abl in response to DNA damage. Kharbanda, S., Pandey, P., Jin, S., Inoue, S., Bharti, A., Yuan, Z.M., Weichselbaum, R., Weaver, D., Kufe, D. Nature (1997) [Pubmed]
  27. Regulation of DNA-dependent protein kinase activity by ionizing radiation-activated abl kinase is an ATM-dependent process. Shangary, S., Brown, K.D., Adamson, A.W., Edmonson, S., Ng, B., Pandita, T.K., Yalowich, J., Taccioli, G.E., Baskaran, R. J. Biol. Chem. (2000) [Pubmed]
  28. mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. Hresko, R.C., Mueckler, M. J. Biol. Chem. (2005) [Pubmed]
  29. p53 is required for both radiation-induced differentiation and rescue of V(D)J rearrangement in scid mouse thymocytes. Bogue, M.A., Zhu, C., Aguilar-Cordova, E., Donehower, L.A., Roth, D.B. Genes Dev. (1996) [Pubmed]
  30. Intracerebral cytokine mRNA expression during fatal and nonfatal alphavirus encephalitis suggests a predominant type 2 T cell response. Wesselingh, S.L., Levine, B., Fox, R.J., Choi, S., Griffin, D.E. J. Immunol. (1994) [Pubmed]
  31. Bcl-2 expression promotes B- but not T-lymphoid development in scid mice. Strasser, A., Harris, A.W., Corcoran, L.M., Cory, S. Nature (1994) [Pubmed]
  32. Sequence-specific binding of Ku autoantigen to single-stranded DNA. Torrance, H., Giffin, W., Rodda, D.J., Pope, L., Haché, R.J. J. Biol. Chem. (1998) [Pubmed]
  33. Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity. Taccioli, G.E., Amatucci, A.G., Beamish, H.J., Gell, D., Xiang, X.H., Torres Arzayus, M.I., Priestley, A., Jackson, S.P., Marshak Rothstein, A., Jeggo, P.A., Herrera, V.L. Immunity (1998) [Pubmed]
  34. Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Rooney, S., Alt, F.W., Sekiguchi, J., Manis, J.P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  35. Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. Gu, Y., Sekiguchi, J., Gao, Y., Dikkes, P., Frank, K., Ferguson, D., Hasty, P., Chun, J., Alt, F.W. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  36. Genetic interaction between DNA polymerase beta and DNA-PKcs in embryogenesis and neurogenesis. Niimi, N., Sugo, N., Aratani, Y., Koyama, H. Cell Death Differ. (2005) [Pubmed]
  37. Xenospecific cytotoxic T lymphocytes: potent lysis in vitro and in vivo. Smyth, M.J., Kershaw, M.H., Trapani, J.A. Transplantation (1997) [Pubmed]
  38. p53 prevents maturation of T cell development to the immature CD4-CD8+ stage in Bcl11b-/- mice. Okazuka, K., Wakabayashi, Y., Kashihara, M., Inoue, J., Sato, T., Yokoyama, M., Aizawa, S., Aizawa, Y., Mishima, Y., Kominami, R. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  39. Membrane-associated CD19-LYN complex is an endogenous p53-independent and Bc1-2-independent regulator of apoptosis in human B-lineage lymphoma cells. Myers, D.E., Jun, X., Waddick, K.G., Forsyth, C., Chelstrom, L.M., Gunther, R.L., Tumer, N.E., Bolen, J., Uckun, F.M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  40. Leishmania donovani infection in scid mice: lack of tissue response and in vivo macrophage activation correlates with failure to trigger natural killer cell-derived gamma interferon production in vitro. Kaye, P.M., Bancroft, G.J. Infect. Immun. (1992) [Pubmed]
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