The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

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

Homo sapiens

Synonyms: DNA-PK catalytic subunit, DNA-PKcs, DNA-dependent protein kinase catalytic subunit, DNAPK, DNPK1, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of PRKDC


High impact information on PRKDC

  • Thus, DNA-PKcs regulates Artemis by both phosphorylation and complex formation to permit enzymatic activities that are critical for the hairpin-opening step of V(D)J recombination and for the 5' and 3' overhang processing in nonhomologous DNA end joining [6].
  • The involvement of inositol phosphate in DNA-PK-dependent NHEJ is of particular interest since the catalytic domain of DNA-PKcs is similar to that found in the phosphatidylinositol 3 (PI 3)-kinase family [7].
  • Mutation of the gene for DNA-PK catalytic subunit (Prkdc) cases defective antigen receptor V(D)J recombination and arrests B- and T-lymphocyte development in severe combined immune-deficiency (SCID) mice [8].
  • DNA-dependent protein kinase (DNA-PK), which is involved in DNA double-stranded break repair and V(D)J recombination, comprises a DNA-targeting component called Ku and an approximately 460 kDa catalytic subunit, DNA-PKcs [9].
  • Strikingly, DNA-PKcs is most similar to PI kinase family members involved in cell cycle control, DNA repair, and DNA damage responses [9].

Chemical compound and disease context of PRKDC


Biological context of PRKDC

  • Differentially expressed probe sets within the DNA repair pathway were consistently overexpressed (93%), with strong effects observed for PRKDC, PCNA, and CHEK1 [11].
  • The promoters for human DNA-PKcs (PRKDC) and MCM4: divergently transcribed genes located at chromosome 8 band q11 [12].
  • M059J is a radiosensitive cell line established from a human glioblastoma tumor that fails to express the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs, now known as PRKDC) [13].
  • Thus the radiosensitive phenotype of M059J cells appears to be due to a defect in PRKDC and a truncating ATM mutation [14].
  • No other sequence differences in PRKDC between M059J and M059K cells were observed in approximately 15,000 bp of genomic sequence including the sequences of exons 5 through 38 and surrounding intron sequence, suggesting a possible reduction to homozygosity at this locus prior to acquisition of the mutation leading to the M059J cell line [15].

Anatomical context of PRKDC


Associations of PRKDC with chemical compounds


Physical interactions of PRKDC

  • DNA-PKcs interacted directly with RPA1 in vitro [23].
  • The atomic structure of a truncated Ku70-Ku80 was determined; however, the subunit-specific carboxy-terminal domain of Ku80-essential for binding to DNA-PKcs-was determined only in isolation, and the C-terminal domain of Ku70 was not resolved in its DNA-bound conformation [24].
  • Here, we report that Artemis forms a complex with the 469 kDa DNA-dependent protein kinase (DNA-PKcs) in the absence of DNA [6].
  • Here, we show that MDC1 directly interacts with the Ku/DNA-PKcs complex [25].
  • First, we showed that WRN forms a complex with DNA-PKcs and Ku in solution [26].

Enzymatic interactions of PRKDC

  • Furthermore, DNA-PKcs was cleaved in vitro by purified apopain (CPP32), but not IL-1beta-converting enzyme [16].
  • WRN is phosphorylated in vivo after treatment of cells with DNA-damaging agents in a pathway that requires DNA-PKcs [27].
  • Upon complex formation, DNA-PKcs phosphorylates Artemis, and Artemis acquires endonucleolytic activity on 5' and 3' overhangs, as well as hairpins [6].
  • DNA-PKcs that was bound to EBNA-LP phosphorylated p53 or EBNA-LP in vitro, and the phosphorylation of EBNA-LP was inhibited by Wortmannin, a specific in vitro inhibitor of DNA-PKcs [28].
  • Here we show that replication stress leads to focus formation of Rad51 and phosphorylated DNA-PKcs, key components of the homologous recombination (HR) and nonhomologous end-joining (NHEJ), double-strand break (DSB) repair pathways, respectively [29].

Co-localisations of PRKDC


Regulatory relationships of PRKDC


Other interactions of PRKDC

  • Ku70/Ku80 and DNA-dependent protein kinase catalytic subunit modulate RAG-mediated cleavage: implications for the enforcement of the 12/23 rule [36].
  • Modulation of cleavage by Ku70/80 and DNA-PKcs results in preferential inhibition of 12/12 and 23/23 DNA cleavage, thus increasing 12/23 rule specificity [36].
  • In addition, under p460 kinase permissive conditions, XRCC4 is detected at DNA ends in a phosphorylated form [37].
  • CONCLUSION: Targeting of the EGFR-dependent PI3K-AKT pathway in K-RAS-mutated A549 cells significantly affects postradiation survival by affecting the activation of DNA-PKcs, resulting in a decreased DSB repair capacity [31].
  • The MCM4 and DNA-PKcs promoters are in CpG islands separated by approximately 700 bp, and transcription from each initiates at multiple, closely spaced sites [12].
  • Although DNA-PKcs autophosphorylates itself at Ser-2056 after IR, we have reported here that ATM mediates DNA-PKcs phosphorylation at Thr-2609 as well as at the adjacent (S/T)Q motifs within the Thr-2609 cluster [38].

Analytical, diagnostic and therapeutic context of PRKDC

  • Sequence analysis of PCR-amplified exons revealed the loss in M059J cells of a single "A" nucleotide in exon 32, corresponding to the first nucleotide of codon 1351 (ACC, Thr) of PRKDC [15].
  • Here, by monitoring protein assembly from human nuclear cell extracts on DNA ends in vitro, we report that recruitment to DNA ends of the XRCC4-ligase IV complex responsible for the key ligation step is strictly dependent on the assembly of both the Ku and p460 components of DNA-PK to these ends [37].
  • Based on co-immunoprecipitation experiments, we conclude that interactions of Ku and p460 with components of the XRCC4-ligase IV complex are mainly DNA-dependent [37].
  • Here we show, using electron spectroscopic imaging, that DNA-PKcs and Ku interact with multiple DNA molecules to form large protein-DNA complexes that converge at the base of multiple DNA loops [21].
  • The primary aim of this study was to investigate if the expression of the DNA damage identifying protein DNA-PKcs known to be involved in DNA repair after treatment with ionising radiation can be used as a predictive marker for radiotherapy (RT) response in cervical cancer [17].


  1. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. Feng, J., Park, J., Cron, P., Hess, D., Hemmings, B.A. J. Biol. Chem. (2004) [Pubmed]
  2. Doxazosin induces apoptosis in LNCaP prostate cancer cell line through DNA binding and DNA-dependent protein kinase down-regulation. Arencibia, J.M., Del Rio, M., Bonnin, A., Lopes, R., Lemoine, N.R., López-Barahona, M. Int. J. Oncol. (2005) [Pubmed]
  3. Potentiality of DNA-dependent protein kinase to phosphorylate Ser46 of human p53. Komiyama, S., Taniguchi, S., Matsumoto, Y., Tsunoda, E., Ohto, T., Suzuki, Y., Yin, H.L., Tomita, M., Enomoto, A., Morita, A., Suzuki, T., Ohtomo, K., Hosoi, Y., Suzuki, N. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  4. Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway. Deriano, L., Guipaud, O., Merle-Béral, H., Binet, J.L., Ricoul, M., Potocki-Veronese, G., Favaudon, V., Maciorowski, Z., Muller, C., Salles, B., Sabatier, L., Delic, J. Blood (2005) [Pubmed]
  5. Allotype imbalance or microsatellite mutation in low-grade soft tissue sarcomas of the extremities in adults. Cho, N.H., Cordon-Cardo, C., Li, G.C., Kim, S.H. J. Pathol. (2002) [Pubmed]
  6. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Ma, Y., Pannicke, U., Schwarz, K., Lieber, M.R. Cell (2002) [Pubmed]
  7. Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair. Hanakahi, L.A., Bartlet-Jones, M., Chappell, C., Pappin, D., West, S.C. Cell (2000) [Pubmed]
  8. Genetic interaction between PARP and DNA-PK in V(D)J recombination and tumorigenesis. Morrison, C., Smith, G.C., Stingl, L., Jackson, S.P., Wagner, E.F., Wang, Z.Q. Nat. Genet. (1997) [Pubmed]
  9. DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Hartley, K.O., Gell, D., Smith, G.C., Zhang, H., Divecha, N., Connelly, M.A., Admon, A., Lees-Miller, S.P., Anderson, C.W., Jackson, S.P. Cell (1995) [Pubmed]
  10. Inhibition of nuclear factor-kappaB and nitric oxide by curcumin induces G2/M cell cycle arrest and apoptosis in human melanoma cells. Zheng, M., Ekmekcioglu, S., Walch, E.T., Tang, C.H., Grimm, E.A. Melanoma Res. (2004) [Pubmed]
  11. Genes involved in DNA repair and nitrosamine metabolism and those located on chromosome 14q32 are dysregulated in nasopharyngeal carcinoma. Dodd, L.E., Sengupta, S., Chen, I.H., den Boon, J.A., Cheng, Y.J., Westra, W., Newton, M.A., Mittl, B.F., McShane, L., Chen, C.J., Ahlquist, P., Hildesheim, A. Cancer Epidemiol. Biomarkers Prev. (2006) [Pubmed]
  12. The promoters for human DNA-PKcs (PRKDC) and MCM4: divergently transcribed genes located at chromosome 8 band q11. Connelly, M.A., Zhang, H., Kieleczawa, J., Anderson, C.W. Genomics (1998) [Pubmed]
  13. Complementation of the radiosensitive M059J cell line. Hoppe, B.S., Jensen, R.B., Kirchgessner, C.U. Radiat. Res. (2000) [Pubmed]
  14. Detection of ATM gene mutation in human glioma cell line M059J by a rapid frameshift/stop codon assay in yeast. Tsuchida, R., Yamada, T., Takagi, M., Shimada, A., Ishioka, C., Katsuki, Y., Igarashi, T., Chessa, L., Delia, D., Teraoka, H., Mizutani, S. Radiat. Res. (2002) [Pubmed]
  15. Frameshift mutation in PRKDC, the gene for DNA-PKcs, in the DNA repair-defective, human, glioma-derived cell line M059J. Anderson, C.W., Dunn, J.J., Freimuth, P.I., Galloway, A.M., Allalunis-Turner, M.J. Radiat. Res. (2001) [Pubmed]
  16. The DNA-dependent protein kinase catalytic subunit (p460) is cleaved during Fas-mediated apoptosis in Jurkat cells. McConnell, K.R., Dynan, W.S., Hardin, J.A. J. Immunol. (1997) [Pubmed]
  17. Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB-IIA of cervical cancer. Beskow, C., Kanter, L., Holgersson, A., Nilsson, B., Frankendal, B., Avall-Lundqvist, E., Lewensohn, R. Br. J. Cancer (2006) [Pubmed]
  18. The catalytic subunit DNA-dependent protein kinase (DNA-PKcs) facilitates recovery from radiation-induced inhibition of DNA replication. Guan, J., DiBiase, S., Iliakis, G. Nucleic Acids Res. (2000) [Pubmed]
  19. Deficiency in the catalytic subunit of DNA-dependent protein kinase causes down-regulation of ATM. Peng, Y., Woods, R.G., Beamish, H., Ye, R., Lees-Miller, S.P., Lavin, M.F., Bedford, J.S. Cancer Res. (2005) [Pubmed]
  20. Enhanced phosphorylation of p53 serine 18 following DNA damage in DNA-dependent protein kinase catalytic subunit-deficient cells. Araki, R., Fukumura, R., Fujimori, A., Taya, Y., Shiloh, Y., Kurimasa, A., Burma, S., Li, G.C., Chen, D.J., Sato, K., Hoki, Y., Tatsumi, K., Abe, M. Cancer Res. (1999) [Pubmed]
  21. The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation. Merkle, D., Douglas, P., Moorhead, G.B., Leonenko, Z., Yu, Y., Cramb, D., Bazett-Jones, D.P., Lees-Miller, S.P. Biochemistry (2002) [Pubmed]
  22. Selective inhibition of the DNA-dependent protein kinase (DNA-PK) by the radiosensitizing agent caffeine. Block, W.D., Merkle, D., Meek, K., Lees-Miller, S.P. Nucleic Acids Res. (2004) [Pubmed]
  23. Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes. Shao, R.G., Cao, C.X., Zhang, H., Kohn, K.W., Wold, M.S., Pommier, Y. EMBO J. (1999) [Pubmed]
  24. Structural model of full-length human Ku70-Ku80 heterodimer and its recognition of DNA and DNA-PKcs. Rivera-Calzada, A., Spagnolo, L., Pearl, L.H., Llorca, O. EMBO Rep. (2007) [Pubmed]
  25. MDC1 regulates DNA-PK autophosphorylation in response to DNA damage. Lou, Z., Chen, B.P., Asaithamby, A., Minter-Dykhouse, K., Chen, D.J., Chen, J. J. Biol. Chem. (2004) [Pubmed]
  26. Displacement of DNA-PKcs from DNA ends by the Werner syndrome protein. Li, B., Comai, L. Nucleic Acids Res. (2002) [Pubmed]
  27. Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation. Karmakar, P., Piotrowski, J., Brosh, R.M., Sommers, J.A., Miller, S.P., Cheng, W.H., Snowden, C.M., Ramsden, D.A., Bohr, V.A. J. Biol. Chem. (2002) [Pubmed]
  28. EBNA-LP associates with cellular proteins including DNA-PK and HA95. Han, I., Harada, S., Weaver, D., Xue, Y., Lane, W., Orstavik, S., Skalhegg, B., Kieff, E. J. Virol. (2001) [Pubmed]
  29. Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Schwartz, M., Zlotorynski, E., Goldberg, M., Ozeri, E., Rahat, A., le Sage, C., Chen, B.P., Chen, D.J., Agami, R., Kerem, B. Genes Dev. (2005) [Pubmed]
  30. Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Chan, D.W., Chen, B.P., Prithivirajsingh, S., Kurimasa, A., Story, M.D., Qin, J., Chen, D.J. Genes Dev. (2002) [Pubmed]
  31. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Toulany, M., Kasten-Pisula, U., Brammer, I., Wang, S., Chen, J., Dittmann, K., Baumann, M., Dikomey, E., Rodemann, H.P. Clin. Cancer Res. (2006) [Pubmed]
  32. Ionizing radiation exposure results in up-regulation of Ku70 via a p53/ataxia-telangiectasia-mutated protein-dependent mechanism. Brown, K.D., Lataxes, T.A., Shangary, S., Mannino, J.L., Giardina, J.F., Chen, J., Baskaran, R. J. Biol. Chem. (2000) [Pubmed]
  33. The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis. Ma, Y., Pannicke, U., Lu, H., Niewolik, D., Schwarz, K., Lieber, M.R. J. Biol. Chem. (2005) [Pubmed]
  34. Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. Chen, L., Trujillo, K., Sung, P., Tomkinson, A.E. J. Biol. Chem. (2000) [Pubmed]
  35. Expression of Ku86 confers favorable outcome of tonsillar carcinoma treated with radiotherapy. Friesland, S., Kanter-Lewensohn, L., Tell, R., Munck-Wikland, E., Lewensohn, R., Nilsson, A. Head & neck. (2003) [Pubmed]
  36. Ku70/Ku80 and DNA-dependent protein kinase catalytic subunit modulate RAG-mediated cleavage: implications for the enforcement of the 12/23 rule. Sawchuk, D.J., Mansilla-Soto, J., Alarcon, C., Singha, N.C., Langen, H., Bianchi, M.E., Lees-Miller, S.P., Nussenzweig, M.C., Cortes, P. J. Biol. Chem. (2004) [Pubmed]
  37. Coordinated assembly of Ku and p460 subunits of the DNA-dependent protein kinase on DNA ends is necessary for XRCC4-ligase IV recruitment. Calsou, P., Delteil, C., Frit, P., Drouet, J., Salles, B. J. Mol. Biol. (2003) [Pubmed]
  38. Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break. Chen, B.P., Uematsu, N., Kobayashi, J., Lerenthal, Y., Krempler, A., Yajima, H., Löbrich, M., Shiloh, Y., Chen, D.J. J. Biol. Chem. (2007) [Pubmed]
WikiGenes - Universities