RBCC Red Blood Cell Collection

PRKDC (HYRC, HYRC1) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
DNA-dependent protein kinase catalytic subunit; DNA-PK catalytic subunit; DNA-PKcs; 2.7.11.1 (DNPK1; p460)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P78527
ID PRKDC_HUMAN Reviewed; 4128 AA.
AC P78527; P78528; Q13327; Q13337; Q14175; Q59H99; Q7Z611; Q96SE6;
read moreAC Q9UME3;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2003, sequence version 3.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=DNA-dependent protein kinase catalytic subunit;
DE Short=DNA-PK catalytic subunit;
DE Short=DNA-PKcs;
DE EC=2.7.11.1;
DE AltName: Full=DNPK1;
DE AltName: Full=p460;
GN Name=PRKDC; Synonyms=HYRC, HYRC1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Cervix carcinoma;
RX PubMed=7671312; DOI=10.1016/0092-8674(95)90482-4;
RA Hartley K.O., Gell D., Smith G.C.M., Zhang H., Divecha N.,
RA Connelly M.A., Admon A., Lees-Miller S.P., Anderson C.W.,
RA Jackson S.P.;
RT "DNA-dependent protein kinase catalytic subunit: a relative of
RT phosphatidylinositol 3-kinase and the ataxia telangiectasia gene
RT product.";
RL Cell 82:849-856(1995).
RN [2]
RP SEQUENCE REVISION, AND ALTERNATIVE SPLICING.
RA Gell D., Anderson C.W.;
RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-6; ILE-333;
RP SER-605; MET-680; SER-695; SER-1071; VAL-1314; VAL-1588; HIS-1603;
RP VAL-2095; GLU-2702; CYS-2899; ASP-3149; SER-3201; GLU-3404; THR-3434;
RP SER-3459; MET-3562; LEU-3836 AND VAL-3932.
RG NIEHS SNPs program;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-1689.
RX PubMed=11418067;
RA Anderson C.W., Dunn J.J., Freimuth P.I., Galloway A.M.,
RA Allalunis-Turner M.J.;
RT "Frameshift mutation in PRKDC, the gene for DNA-PKcs, in the DNA
RT repair-defective, human, glioma-derived cell line M059J.";
RL Radiat. Res. 156:2-9(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-49.
RX PubMed=9284934;
RA Ladenburger E.M., Fackelmayer F.O., Hameister H., Knippers R.;
RT "MCM4 and PRKDC, human genes encoding proteins MCM4 and DNA-PKcs, are
RT close neighbours located on chromosome 8q12-->q13.";
RL Cytogenet. Cell Genet. 77:268-270(1997).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1789-2203.
RC TISSUE=Placenta;
RX PubMed=7638222; DOI=10.1073/pnas.92.16.7515;
RA Sipley J.D., Menninger J.C., Hartley K.O., Ward D.C., Jackson S.P.,
RA Anderson C.W.;
RT "Gene for the catalytic subunit of the human DNA-activated protein
RT kinase maps to the site of the XRCC7 gene on chromosome 8.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7515-7519(1995).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 2255-2335.
RC TISSUE=Placenta;
RA Abe M.;
RL Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3199-4128 (ISOFORM 1).
RC TISSUE=Fetal lung;
RX PubMed=7594449;
RA Poltoratsky V.P., Shi X., York J.D., Lieber M.R., Carter T.H.;
RT "Human DNA-activated protein kinase (DNA-PK) is homologous to
RT phosphatidylinositol kinases.";
RL J. Immunol. 155:4529-4533(1995).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 3250-4128 (ISOFORM 1).
RA Anderson C.W., Dunn J.J., Freimuth P.I.;
RT "Sequence of the 3' segment (exons 70-86) of PRKDC, the gene for human
RT DNA-PKcs.";
RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3372-4128 (ISOFORM 2).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno F.R.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP PHOSPHORYLATION OF HSPCA.
RX PubMed=2507541;
RA Lees-Miller S.P., Anderson C.W.;
RT "The human double-stranded DNA-activated protein kinase phosphorylates
RT the 90-kDa heat-shock protein, hsp90 alpha at two NH2-terminal
RT threonine residues.";
RL J. Biol. Chem. 264:17275-17280(1989).
RN [12]
RP PHOSPHORYLATION OF H1.
RX PubMed=2247066;
RA Carter T., Vancurova I., Sun I., Lou W., DeLeon S.;
RT "A DNA-activated protein kinase from HeLa cell nuclei.";
RL Mol. Cell. Biol. 10:6460-6471(1990).
RN [13]
RP PHOSPHORYLATION OF MYC.
RX PubMed=1597196; DOI=10.1111/j.1432-1033.1992.tb16964.x;
RA Iijima S., Teraoka H., Date T., Tsukada K.;
RT "DNA-activated protein kinase in Raji Burkitt's lymphoma cells.
RT Phosphorylation of c-Myc oncoprotein.";
RL Eur. J. Biochem. 206:595-603(1992).
RN [14]
RP PHOSPHORYLATION OF SRF.
RX PubMed=8407951;
RA Liu S.-H., Ma J.-T., Yueh A.Y., Lees-Miller S.P., Anderson C.W.,
RA Ng S.-Y.;
RT "The carboxyl-terminal transactivation domain of human serum response
RT factor contains DNA-activated protein kinase phosphorylation sites.";
RL J. Biol. Chem. 268:21147-21154(1993).
RN [15]
RP PHOSPHORYLATION OF JUN.
RX PubMed=8464713; DOI=10.1093/nar/21.5.1289;
RA Bannister A.J., Gottlieb T.M., Kouzarides T., Jackson S.P.;
RT "c-Jun is phosphorylated by the DNA-dependent protein kinase in vitro;
RT definition of the minimal kinase recognition motif.";
RL Nucleic Acids Res. 21:1289-1295(1993).
RN [16]
RP CLEAVAGE BY CASPASE-3.
RX PubMed=8804412; DOI=10.1016/0014-5793(96)00842-3;
RA Teraoka H., Yumoto Y., Watanabe F., Tsukada K., Suwa A., Enari M.,
RA Nagata S.;
RT "CPP32/Yama/apopain cleaves the catalytic component of DNA-dependent
RT protein kinase in the holoenzyme.";
RL FEBS Lett. 393:1-6(1996).
RN [17]
RP ALTERNATIVE SPLICING.
RX PubMed=8917110; DOI=10.1016/0378-1119(96)00135-7;
RA Connelly M.A., Zhang H., Kieleczawa J., Anderson C.W.;
RT "Alternate splice-site utilization in the gene for the catalytic
RT subunit of the DNA-activated protein kinase, DNA-PKcs.";
RL Gene 175:271-273(1996).
RN [18]
RP PHOSPHORYLATION OF TP53.
RX PubMed=9363941; DOI=10.1016/S0092-8674(00)80416-X;
RA Shieh S.-Y., Ikeda M., Taya Y., Prives C.;
RT "DNA damage-induced phosphorylation of p53 alleviates inhibition by
RT MDM2.";
RL Cell 91:325-334(1997).
RN [19]
RP CHARACTERIZATION.
RX PubMed=9372844; DOI=10.1016/S0921-8777(97)00035-9;
RA Wu X., Lieber M.R.;
RT "Interaction between DNA-dependent protein kinase and a novel protein,
RT KIP.";
RL Mutat. Res. 385:13-20(1997).
RN [20]
RP PHOSPHORYLATION OF XRCC6.
RX PubMed=9362500; DOI=10.1093/emboj/16.22.6874;
RA Jin S., Weaver D.T.;
RT "Double-strand break repair by Ku70 requires heterodimerization with
RT Ku80 and DNA binding functions.";
RL EMBO J. 16:6874-6885(1997).
RN [21]
RP PHOSPHORYLATION OF RFA2.
RX PubMed=9139719; DOI=10.1074/jbc.272.19.12634;
RA Niu H., Erdjument-Bromage H., Pan Z.-Q., Lee S.-H., Tempst P.,
RA Hurwitz J.;
RT "Mapping of amino acid residues in the p34 subunit of human single-
RT stranded DNA-binding protein phosphorylated by DNA-dependent protein
RT kinase and Cdc2 kinase in vitro.";
RL J. Biol. Chem. 272:12634-12641(1997).
RN [22]
RP ENZYME REGULATION.
RX PubMed=9766667;
RA Sarkaria J.N., Tibbetts R.S., Busby E.C., Kennedy A.P., Hill D.E.,
RA Abraham R.T.;
RT "Inhibition of phosphoinositide 3-kinase related kinases by the
RT radiosensitizing agent wortmannin.";
RL Cancer Res. 58:4375-4382(1998).
RN [23]
RP FUNCTION, INTERACTION WITH C1D, AND MUTAGENESIS OF LEU-1510 AND
RP 1516-GLU-LEU-1517.
RX PubMed=9679063;
RA Yavuzer U., Smith G.C.M., Bliss T., Werner D., Jackson S.P.;
RT "DNA end-independent activation of DNA-PK mediated via association
RT with the DNA-binding protein C1D.";
RL Genes Dev. 12:2188-2199(1998).
RN [24]
RP INTERACTION WITH ILF3.
RX PubMed=9442054; DOI=10.1074/jbc.273.4.2136;
RA Ting N.S.Y., Kao P.N., Chan D.W., Lintott L.G., Lees-Miller S.P.;
RT "DNA-dependent protein kinase interacts with antigen receptor response
RT element binding proteins NF90 and NF45.";
RL J. Biol. Chem. 273:2136-2145(1998).
RN [25]
RP DNA-BINDING.
RX PubMed=9435225; DOI=10.1073/pnas.95.2.525;
RA Hammarsten O., Chu G.;
RT "DNA-dependent protein kinase: DNA binding and activation in the
RT absence of Ku.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:525-530(1998).
RN [26]
RP PHOSPHORYLATION OF XRCC5 AND XRCC6.
RX PubMed=10026262; DOI=10.1021/bi982584b;
RA Chan D.W., Ye R., Veillette C.J., Lees-Miller S.P.;
RT "DNA-dependent protein kinase phosphorylation sites in Ku 70/80
RT heterodimer.";
RL Biochemistry 38:1819-1828(1999).
RN [27]
RP PHOSPHORYLATION OF PARP1.
RX PubMed=10467406; DOI=10.1038/sj.onc.1202823;
RA Ariumi Y., Masutani M., Copeland T.D., Mimori T., Sugimura T.,
RA Shimotohno K., Ueda K., Hatanaka M., Noda M.;
RT "Suppression of the poly(ADP-ribose) polymerase activity by DNA-
RT dependent protein kinase in vitro.";
RL Oncogene 18:4616-4625(1999).
RN [28]
RP PHOSPHORYLATION AT THR-2609; SER-2612; THR-2638 AND THR-2647.
RX PubMed=12186630; DOI=10.1042/BJ20020973;
RA Douglas P., Sapkota G.P., Morrice N., Yu Y., Goodarzi A.A., Merkle D.,
RA Meek K., Alessi D.R., Lees-Miller S.P.;
RT "Identification of in vitro and in vivo phosphorylation sites in the
RT catalytic subunit of the DNA-dependent protein kinase.";
RL Biochem. J. 368:243-251(2002).
RN [29]
RP INTERACTION WITH DCLRE1C.
RX PubMed=11955432; DOI=10.1016/S0092-8674(02)00671-2;
RA Ma Y., Pannicke U., Schwarz K., Lieber M.R.;
RT "Hairpin opening and overhang processing by an Artemis/DNA-dependent
RT protein kinase complex in nonhomologous end joining and V(D)J
RT recombination.";
RL Cell 108:781-794(2002).
RN [30]
RP PHOSPHORYLATION OF XRCC4.
RX PubMed=12509254; DOI=10.1016/S1568-7864(01)00018-0;
RA Hsu H.-L., Yannone S.M., Chen D.J.;
RT "Defining interactions between DNA-PK and ligase IV/XRCC4.";
RL DNA Repair 1:225-235(2002).
RN [31]
RP MASS SPECTROMETRY, PHOSPHORYLATION AT THR-2609, MUTAGENESIS OF
RP THR-2609, AND SUBCELLULAR LOCATION.
RX PubMed=12231622; DOI=10.1101/gad.1015202;
RA Chan D.W., Chen B.P., Prithivirajsingh S., Kurimasa A., Story M.D.,
RA Qin J., Chen D.J.;
RT "Autophosphorylation of the DNA-dependent protein kinase catalytic
RT subunit is required for rejoining of DNA double-strand breaks.";
RL Genes Dev. 16:2333-2338(2002).
RN [32]
RP PHOSPHORYLATION OF WRN.
RX PubMed=11889123; DOI=10.1074/jbc.M111523200;
RA Karmakar P., Piotrowski J., Brosh R.M. Jr., Sommers J.A., Miller S.P.,
RA Cheng W.H., Snowden C.M., Ramsden D.A., Bohr V.A.;
RT "Werner protein is a target of DNA-dependent protein kinase in vivo
RT and in vitro, and its catalytic activities are regulated by
RT phosphorylation.";
RL J. Biol. Chem. 277:18291-18302(2002).
RN [33]
RP FUNCTION, AND MUTAGENESIS OF THR-2638 AND THR-2647.
RX PubMed=12649176;
RA Soubeyrand S., Pope L., Pakuts B., Hache R.J.;
RT "Threonines 2638/2647 in DNA-PK are essential for cellular resistance
RT to ionizing radiation.";
RL Cancer Res. 63:1198-1201(2003).
RN [34]
RP PHOSPHORYLATION OF POU2F1.
RX PubMed=14612514;
RA Schild-Poulter C., Shih A., Yarymowich N.C., Hache R.J.G.;
RT "Down-regulation of histone H2B by DNA-dependent protein kinase in
RT response to DNA damage through modulation of octamer transcription
RT factor 1.";
RL Cancer Res. 63:7197-7205(2003).
RN [35]
RP PHOSPHORYLATION OF H2AFX.
RX PubMed=14627815; DOI=10.1093/nar/gkg921;
RA Park E.-J., Chan D.W., Park J.-H., Oettinger M.A., Kwon J.;
RT "DNA-PK is activated by nucleosomes and phosphorylates H2AX within the
RT nucleosomes in an acetylation-dependent manner.";
RL Nucleic Acids Res. 31:6819-6827(2003).
RN [36]
RP INTERACTION WITH DCLRE1C.
RX PubMed=15071507; DOI=10.1038/sj.emboj.7600206;
RA Pannicke U., Ma Y., Hopfner K.-P., Niewolik D., Lieber M.R.,
RA Schwarz K.;
RT "Functional and biochemical dissection of the structure-specific
RT nuclease ARTEMIS.";
RL EMBO J. 23:1987-1997(2004).
RN [37]
RP INTERACTION WITH DCLRE1C.
RX PubMed=14744996; DOI=10.1084/jem.20031142;
RA Poinsignon C., Moshous D., Callebaut I., de Chasseval R., Villey I.,
RA de Villartay J.-P.;
RT "The metallo-beta-lactamase/beta-CASP domain of Artemis constitutes
RT the catalytic core for V(D)J recombination.";
RL J. Exp. Med. 199:315-321(2004).
RN [38]
RP FUNCTION, AND INTERACTION WITH DCLRE1C.
RX PubMed=15574326; DOI=10.1016/j.molcel.2004.11.017;
RA Ma Y., Lu H., Tippin B., Goodman M.F., Shimazaki N., Koiwai O.,
RA Hsieh C.-L., Schwarz K., Lieber M.R.;
RT "A biochemically defined system for mammalian nonhomologous DNA end
RT joining.";
RL Mol. Cell 16:701-713(2004).
RN [39]
RP INTERACTION WITH DCLRE1C.
RX PubMed=15456891; DOI=10.1128/MCB.24.20.9207-9220.2004;
RA Zhang X., Succi J., Feng Z., Prithivirajsingh S., Story M.D.,
RA Legerski R.J.;
RT "Artemis is a phosphorylation target of ATM and ATR and is involved in
RT the G2/M DNA damage checkpoint response.";
RL Mol. Cell. Biol. 24:9207-9220(2004).
RN [40]
RP PHOSPHORYLATION OF DHX9.
RX PubMed=14704337; DOI=10.1093/nar/gkg933;
RA Zhang S., Schlott B., Goerlach M., Grosse F.;
RT "DNA-dependent protein kinase (DNA-PK) phosphorylates nuclear DNA
RT helicase II/RNA helicase A and hnRNP proteins in an RNA-dependent
RT manner.";
RL Nucleic Acids Res. 32:1-10(2004).
RN [41]
RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-2056 AND
RP THR-2609, AND DEPHOSPHORYLATION AT SER-2056 AND THR-2609.
RX PubMed=14734805; DOI=10.1073/pnas.0307765100;
RA Wechsler T., Chen B.P., Harper R., Morotomi-Yano K., Huang B.C.,
RA Meek K., Cleaver J.E., Chen D.J., Wabl M.;
RT "DNA-PKcs function regulated specifically by protein phosphatase 5.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:1247-1252(2004).
RN [42]
RP PHOSPHORYLATION OF H2AFX.
RX PubMed=16046194; DOI=10.1016/j.dnarep.2005.06.005;
RA Reitsema T., Klokov D., Banath J.P., Olive P.L.;
RT "DNA-PK is responsible for enhanced phosphorylation of histone H2AX
RT under hypertonic conditions.";
RL DNA Repair 4:1172-1181(2005).
RN [43]
RP INTERACTION WITH DCLRE1C.
RX PubMed=15811628; DOI=10.1016/j.dnarep.2005.02.001;
RA Wang J., Pluth J.M., Cooper P.K., Cowan M.J., Chen D.J., Yannone S.M.;
RT "Artemis deficiency confers a DNA double-strand break repair defect
RT and Artemis phosphorylation status is altered by DNA damage and cell
RT cycle progression.";
RL DNA Repair 4:556-570(2005).
RN [44]
RP INTERACTION WITH DCLRE1C.
RX PubMed=15936993; DOI=10.1016/j.dnarep.2005.04.013;
RA Ma Y., Schwarz K., Lieber M.R.;
RT "The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and
RT gaps.";
RL DNA Repair 4:845-851(2005).
RN [45]
RP INTERACTION WITH XRCC5.
RX PubMed=15758953; DOI=10.1038/nature03442;
RA Falck J., Coates J., Jackson S.P.;
RT "Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of
RT DNA damage.";
RL Nature 434:605-611(2005).
RN [46]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3205, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [47]
RP PHOSPHORYLATION OF XRCC1.
RX PubMed=16397295; DOI=10.1093/nar/gkj409;
RA Levy N., Martz A., Bresson A., Spenlehauer C., de Murcia G.,
RA Menissier-de Murcia J.;
RT "XRCC1 is phosphorylated by DNA-dependent protein kinase in response
RT to DNA damage.";
RL Nucleic Acids Res. 34:32-41(2006).
RN [48]
RP REVIEW.
RX PubMed=15592499; DOI=10.1038/sj.onc.1208332;
RA Collis S.J., DeWeese T.L., Jeggo P.A., Parker A.R.;
RT "The life and death of DNA-PK.";
RL Oncogene 24:949-961(2005).
RN [49]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [50]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3205 AND SER-4026, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [51]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3205, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [52]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-893; SER-2612; SER-3205
RP AND SER-4026, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [53]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3205, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [54]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-117; LYS-828; LYS-1209;
RP LYS-1970; LYS-2259; LYS-3241; LYS-3260; LYS-3621; LYS-3638 AND
RP LYS-3642, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [55]
RP INTERACTION WITH TTI1.
RX PubMed=20810650; DOI=10.1101/gad.1934210;
RA Hurov K.E., Cotta-Ramusino C., Elledge S.J.;
RT "A genetic screen identifies the Triple T complex required for DNA
RT damage signaling and ATM and ATR stability.";
RL Genes Dev. 24:1939-1950(2010).
RN [56]
RP INTERACTION WITH TELO2.
RX PubMed=20801936; DOI=10.1101/gad.1956410;
RA Takai H., Xie Y., de Lange T., Pavletich N.P.;
RT "Tel2 structure and function in the Hsp90-dependent maturation of mTOR
RT and ATR complexes.";
RL Genes Dev. 24:2019-2030(2010).
RN [57]
RP INTERACTION WITH TELO2 AND TTI1.
RX PubMed=20427287; DOI=10.1074/jbc.M110.121699;
RA Kaizuka T., Hara T., Oshiro N., Kikkawa U., Yonezawa K., Takehana K.,
RA Iemura S., Natsume T., Mizushima N.;
RT "Tti1 and Tel2 are critical factors in mammalian target of rapamycin
RT complex assembly.";
RL J. Biol. Chem. 285:20109-20116(2010).
RN [58]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3205 AND SER-4026, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [59]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [60]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2612 AND SER-3205, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [61]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RX PubMed=22002106; DOI=10.1074/mcp.M111.013680;
RA Ahmad Y., Boisvert F.M., Lundberg E., Uhlen M., Lamond A.I.;
RT "Systematic analysis of protein pools, isoforms, and modifications
RT affecting turnover and subcellular localization.";
RL Mol. Cell. Proteomics 11:M111.013680.01-M111.013680.15(2012).
RN [62]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-6; ASN-263; ILE-333; ILE-420;
RP SER-500; SER-605; LEU-649; SER-695; HIS-1136; VAL-1190; THR-1237;
RP PHE-1279; MET-1447; GLY-1619; VAL-1680; VAL-1680; PRO-2023; GLN-2598;
RP ASN-2810; CYS-2899; ALA-2941; ASP-3085; ASP-3149; SER-3198; SER-3201;
RP GLU-3404; THR-3434; MET-3562; PHE-3584; ILE-3800; LEU-3836; SER-3936
RP AND MET-3937.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase that acts as a molecular
CC sensor for DNA damage. Involved in DNA nonhomologous end joining
CC (NHEJ) required for double-strand break (DSB) repair and V(D)J
CC recombination. Must be bound to DNA to express its catalytic
CC properties. Promotes processing of hairpin DNA structures in V(D)J
CC recombination by activation of the hairpin endonuclease artemis
CC (DCLRE1C). The assembly of the DNA-PK complex at DNA ends is also
CC required for the NHEJ ligation step. Required to protect and align
CC broken ends of DNA. May also act as a scaffold protein to aid the
CC localization of DNA repair proteins to the site of damage. Found
CC at the ends of chromosomes, suggesting a further role in the
CC maintenance of telomeric stability and the prevention of
CC chromosomal end fusion. Also involved in modulation of
CC transcription. Recognizes the substrate consensus sequence [ST]-Q.
CC Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX, thereby
CC regulating DNA damage response mechanism. Phosphorylates DCLRE1C,
CC c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1,
CC DHX9, SRF, XRCC1, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2.
CC Can phosphorylate C1D not only in the presence of linear DNA but
CC also in the presence of supercoiled DNA. Ability to phosphorylate
CC p53/TP53 in the presence of supercoiled DNA is dependent on C1D.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Inhibited by wortmannin. Activity of the enzyme
CC seems to be attenuated by autophosphorylation.
CC -!- SUBUNIT: DNA-PK is a heterotrimer of PRKDC and the Ku p70-p86
CC (XRCC6-XRCC5) dimer. Formation of this complex may be promoted by
CC interaction with ILF3. Associates with the DNA-bound Ku
CC heterodimer, but it can also bind to and be activated by free DNA.
CC Interacts with DNA-PKcs-interacting protein (KIP) with the region
CC upstream the kinase domain. PRKDC alone also interacts with and
CC phosphorylates DCLRE1C, thereby activating the latent endonuclease
CC activity of this protein. Interacts with C1D. Interacts with TTI1
CC and TELO2.
CC -!- INTERACTION:
CC O43918:AIRE; NbExp=2; IntAct=EBI-352053, EBI-1753081;
CC P42575:CASP2; NbExp=4; IntAct=EBI-352053, EBI-520342;
CC P14921:ETS1; NbExp=2; IntAct=EBI-352053, EBI-913209;
CC P50549:ETV1; NbExp=2; IntAct=EBI-352053, EBI-3905068;
CC P09629:HOXB7; NbExp=2; IntAct=EBI-352053, EBI-1248457;
CC Q9HB75:PIDD; NbExp=6; IntAct=EBI-352053, EBI-520427;
CC P17947:SPI1; NbExp=2; IntAct=EBI-352053, EBI-2293548;
CC P13010:XRCC5; NbExp=6; IntAct=EBI-352053, EBI-357997;
CC P12956:XRCC6; NbExp=5; IntAct=EBI-352053, EBI-353208;
CC P25490:YY1; NbExp=2; IntAct=EBI-352053, EBI-765538;
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus, nucleolus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P78527-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P78527-2; Sequence=VSP_004708;
CC -!- PTM: Autophosphorylated on Ser-2056, Thr-2609, Thr-2638 and Thr-
CC 2647. Ser-2056 and Thr-2609 are DNA damage-inducible
CC phosphorylation sites (inducible with ionizing radiation, IR)
CC dephosphorylated by PPP5C. Autophosphorylation induces a
CC conformational change that leads to remodeling of the DNA-PK
CC complex, requisite for efficient end processing and DNA repair.
CC -!- PTM: S-nitrosylated by GAPDH (By similarity).
CC -!- SIMILARITY: Belongs to the PI3/PI4-kinase family.
CC -!- SIMILARITY: Contains 1 FAT domain.
CC -!- SIMILARITY: Contains 1 FATC domain.
CC -!- SIMILARITY: Contains 2 HEAT repeats.
CC -!- SIMILARITY: Contains 1 PI3K/PI4K domain.
CC -!- SIMILARITY: Contains 3 TPR repeats.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/prkdc/";
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DR EMBL; U47077; AAB39925.5; -; mRNA.
DR EMBL; U34994; AAC50210.3; -; mRNA.
DR EMBL; AY316117; AAP69525.1; -; Genomic_DNA.
DR EMBL; U63630; AAC52019.2; -; Genomic_DNA.
DR EMBL; U90415; AAB51722.1; -; Genomic_DNA.
DR EMBL; L27425; AAA79244.1; -; Genomic_DNA.
DR EMBL; AB052953; BAB79635.1; -; Genomic_DNA.
DR EMBL; U35835; AAA79184.1; -; mRNA.
DR EMBL; AY030284; AAK40350.1; -; Genomic_DNA.
DR EMBL; AB208860; BAD92097.1; -; mRNA.
DR PIR; A57099; A57099.
DR PIR; G02083; G02083.
DR RefSeq; NP_001075109.1; NM_001081640.1.
DR RefSeq; NP_008835.5; NM_006904.6.
DR UniGene; Hs.491682; -.
DR ProteinModelPortal; P78527; -.
DR SMR; P78527; 3724-3998.
DR DIP; DIP-24186N; -.
DR IntAct; P78527; 65.
DR MINT; MINT-5006046; -.
DR BindingDB; P78527; -.
DR ChEMBL; CHEMBL3142; -.
DR PhosphoSite; P78527; -.
DR DMDM; 38258929; -.
DR SWISS-2DPAGE; P78527; -.
DR PaxDb; P78527; -.
DR PRIDE; P78527; -.
DR Ensembl; ENST00000314191; ENSP00000313420; ENSG00000253729.
DR GeneID; 5591; -.
DR KEGG; hsa:5591; -.
DR UCSC; uc003xqi.3; human.
DR CTD; 5591; -.
DR GeneCards; GC08M048685; -.
DR HGNC; HGNC:9413; PRKDC.
DR HPA; CAB005167; -.
DR MIM; 600899; gene.
DR neXtProt; NX_P78527; -.
DR Orphanet; 317425; Severe combined immunodeficiency due to DNA-PKcs deficiency.
DR PharmGKB; PA33776; -.
DR eggNOG; COG5032; -.
DR HOVERGEN; HBG053681; -.
DR InParanoid; P78527; -.
DR KO; K06642; -.
DR OrthoDB; EOG7DNNT7; -.
DR Reactome; REACT_216; DNA Repair.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; PRKDC; human.
DR GeneWiki; DNA-PKcs; -.
DR GenomeRNAi; 5591; -.
DR NextBio; 21692; -.
DR PRO; PR:P78527; -.
DR ArrayExpress; P78527; -.
DR Bgee; P78527; -.
DR Genevestigator; P78527; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005958; C:DNA-dependent protein kinase-DNA ligase 4 complex; IDA:MGI.
DR GO; GO:0005730; C:nucleolus; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005667; C:transcription factor complex; IDA:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0004677; F:DNA-dependent protein kinase activity; IDA:MGI.
DR GO; GO:0006915; P:apoptotic process; IEA:Ensembl.
DR GO; GO:0002326; P:B cell lineage commitment; IEA:Ensembl.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL.
DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; TAS:Reactome.
DR GO; GO:0035234; P:germ cell programmed cell death; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0033152; P:immunoglobulin V(D)J recombination; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IMP:BHF-UCL.
DR GO; GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0002328; P:pro-B cell differentiation; IEA:Ensembl.
DR GO; GO:0031648; P:protein destabilization; IEA:Ensembl.
DR GO; GO:0010332; P:response to gamma radiation; IEA:Ensembl.
DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl.
DR GO; GO:0033077; P:T cell differentiation in thymus; IEA:Ensembl.
DR GO; GO:0002360; P:T cell lineage commitment; IEA:Ensembl.
DR GO; GO:0033153; P:T cell receptor V(D)J recombination; IEA:Ensembl.
DR GO; GO:0000723; P:telomere maintenance; IEA:Ensembl.
DR Gene3D; 1.10.1070.11; -; 3.
DR Gene3D; 1.25.10.10; -; 3.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR003152; FATC.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR012582; NUC194.
DR InterPro; IPR000403; PI3/4_kinase_cat_dom.
DR InterPro; IPR018936; PI3/4_kinase_CS.
DR InterPro; IPR003151; PIK-rel_kinase_FAT.
DR InterPro; IPR014009; PIK_FAT.
DR Pfam; PF02259; FAT; 1.
DR Pfam; PF02260; FATC; 1.
DR Pfam; PF08163; NUC194; 1.
DR Pfam; PF00454; PI3_PI4_kinase; 1.
DR SMART; SM00146; PI3Kc; 1.
DR SUPFAM; SSF48371; SSF48371; 8.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS51189; FAT; 1.
DR PROSITE; PS51190; FATC; 1.
DR PROSITE; PS50077; HEAT_REPEAT; FALSE_NEG.
DR PROSITE; PS00915; PI3_4_KINASE_1; 1.
DR PROSITE; PS00916; PI3_4_KINASE_2; 1.
DR PROSITE; PS50290; PI3_4_KINASE_3; 1.
DR PROSITE; PS50005; TPR; FALSE_NEG.
DR PROSITE; PS50293; TPR_REGION; FALSE_NEG.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; ATP-binding; Complete proteome;
KW DNA damage; DNA recombination; DNA repair; DNA-binding; Kinase;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; S-nitrosylation;
KW Serine/threonine-protein kinase; TPR repeat; Transferase.
FT CHAIN 1 4128 DNA-dependent protein kinase catalytic
FT subunit.
FT /FTId=PRO_0000225598.
FT REPEAT 288 323 HEAT 1.
FT REPEAT 1004 1040 HEAT 2.
FT REPEAT 1723 1756 TPR 1.
FT DOMAIN 2883 3539 FAT.
FT REPEAT 2920 2948 TPR 2.
FT REPEAT 2949 2982 TPR 3.
FT DOMAIN 3747 4015 PI3K/PI4K.
FT DOMAIN 4096 4128 FATC.
FT REGION 1503 1538 Interaction with C1D.
FT REGION 1503 1538 Leucine-zipper.
FT REGION 2436 3212 KIP-binding.
FT SITE 2020 2021 Cleavage; by caspase-3 (Probable).
FT MOD_RES 117 117 N6-acetyllysine.
FT MOD_RES 828 828 N6-acetyllysine.
FT MOD_RES 893 893 Phosphoserine.
FT MOD_RES 1209 1209 N6-acetyllysine.
FT MOD_RES 1970 1970 N6-acetyllysine.
FT MOD_RES 2056 2056 Phosphoserine; by autocatalysis.
FT MOD_RES 2259 2259 N6-acetyllysine.
FT MOD_RES 2609 2609 Phosphothreonine; by autocatalysis.
FT MOD_RES 2612 2612 Phosphoserine; by autocatalysis.
FT MOD_RES 2638 2638 Phosphothreonine; by autocatalysis.
FT MOD_RES 2647 2647 Phosphothreonine; by autocatalysis.
FT MOD_RES 3205 3205 Phosphoserine.
FT MOD_RES 3241 3241 N6-acetyllysine.
FT MOD_RES 3260 3260 N6-acetyllysine.
FT MOD_RES 3621 3621 N6-acetyllysine.
FT MOD_RES 3638 3638 N6-acetyllysine.
FT MOD_RES 3642 3642 N6-acetyllysine.
FT MOD_RES 4026 4026 Phosphoserine.
FT VAR_SEQ 3799 3829 Missing (in isoform 2).
FT /FTId=VSP_004708.
FT VARIANT 6 6 A -> S (in dbSNP:rs8177999).
FT /FTId=VAR_019179.
FT VARIANT 263 263 K -> N (in a lung adenocarcinoma sample;
FT somatic mutation).
FT /FTId=VAR_041602.
FT VARIANT 333 333 M -> I (in dbSNP:rs8178017).
FT /FTId=VAR_019180.
FT VARIANT 420 420 V -> I (in dbSNP:rs55925466).
FT /FTId=VAR_041603.
FT VARIANT 500 500 G -> S (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_041604.
FT VARIANT 605 605 T -> S (in dbSNP:rs8178033).
FT /FTId=VAR_019181.
FT VARIANT 649 649 F -> L (in dbSNP:rs55811715).
FT /FTId=VAR_041605.
FT VARIANT 680 680 I -> M (in dbSNP:rs8178040).
FT /FTId=VAR_019182.
FT VARIANT 695 695 P -> S (in dbSNP:rs8178046).
FT /FTId=VAR_019183.
FT VARIANT 1071 1071 N -> S (in dbSNP:rs8178070).
FT /FTId=VAR_019184.
FT VARIANT 1136 1136 R -> H (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_041606.
FT VARIANT 1190 1190 L -> V (in dbSNP:rs34598508).
FT /FTId=VAR_041607.
FT VARIANT 1237 1237 A -> T.
FT /FTId=VAR_041608.
FT VARIANT 1279 1279 L -> F.
FT /FTId=VAR_041609.
FT VARIANT 1314 1314 G -> V (in dbSNP:rs8178090).
FT /FTId=VAR_019185.
FT VARIANT 1447 1447 R -> M (in a lung squamous cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_041610.
FT VARIANT 1588 1588 D -> V (in dbSNP:rs8178104).
FT /FTId=VAR_019186.
FT VARIANT 1603 1603 Q -> H (in dbSNP:rs8178106).
FT /FTId=VAR_019187.
FT VARIANT 1619 1619 A -> G (in dbSNP:rs56182356).
FT /FTId=VAR_041611.
FT VARIANT 1680 1680 A -> V (in a metastatic melanoma sample;
FT somatic mutation; dbSNP:rs55735910).
FT /FTId=VAR_041612.
FT VARIANT 2023 2023 S -> P (in dbSNP:rs56042895).
FT /FTId=VAR_041613.
FT VARIANT 2095 2095 A -> V (in dbSNP:rs8178147).
FT /FTId=VAR_019188.
FT VARIANT 2598 2598 R -> Q (in dbSNP:rs55923149).
FT /FTId=VAR_041614.
FT VARIANT 2702 2702 K -> E (in dbSNP:rs8178178).
FT /FTId=VAR_019189.
FT VARIANT 2810 2810 S -> N (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_041615.
FT VARIANT 2899 2899 R -> C (in dbSNP:rs4278157).
FT /FTId=VAR_019190.
FT VARIANT 2941 2941 G -> A (in a lung neuroendocrine
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_041616.
FT VARIANT 3085 3085 E -> D (in dbSNP:rs56135402).
FT /FTId=VAR_041617.
FT VARIANT 3149 3149 G -> D (in dbSNP:rs8178208).
FT /FTId=VAR_019191.
FT VARIANT 3198 3198 T -> S (in dbSNP:rs55793951).
FT /FTId=VAR_041618.
FT VARIANT 3201 3201 P -> S (in dbSNP:rs8178216).
FT /FTId=VAR_019192.
FT VARIANT 3404 3404 G -> E (in dbSNP:rs8178225).
FT /FTId=VAR_019193.
FT VARIANT 3434 3434 I -> T (in dbSNP:rs7830743).
FT /FTId=VAR_019194.
FT VARIANT 3459 3459 N -> S (in dbSNP:rs8178228).
FT /FTId=VAR_019195.
FT VARIANT 3562 3562 L -> M (in dbSNP:rs8178232).
FT /FTId=VAR_019196.
FT VARIANT 3584 3584 L -> F.
FT /FTId=VAR_041619.
FT VARIANT 3702 3702 P -> L (in dbSNP:rs8178236).
FT /FTId=VAR_050534.
FT VARIANT 3800 3800 L -> I.
FT /FTId=VAR_041620.
FT VARIANT 3836 3836 P -> L (in dbSNP:rs8178245).
FT /FTId=VAR_019197.
FT VARIANT 3932 3932 M -> V.
FT /FTId=VAR_019198.
FT VARIANT 3936 3936 G -> S.
FT /FTId=VAR_041621.
FT VARIANT 3937 3937 V -> M.
FT /FTId=VAR_041622.
FT MUTAGEN 1510 1510 L->P: Loss of interaction with C1D.
FT MUTAGEN 1516 1517 EL->PD: Loss of interaction with C1D.
FT MUTAGEN 2609 2609 T->A: Leads to radiation sensitivity and
FT impaired DSB joining. Gives rise to
FT reduced phosphorylation; when associated
FT with A-2612.
FT MUTAGEN 2612 2612 S->A: Reduced phosphorylation; when
FT associated with A-2609.
FT MUTAGEN 2638 2638 T->A: Alleviates phosphorylation, leaves
FT a fully active enzyme with compromised
FT cellular resistance to ionizing radiation
FT without affecting DNA end joining; when
FT associated with A-2647.
FT MUTAGEN 2647 2647 T->A: Alleviates phosphorylation, leaves
FT a fully active enzyme with compromised
FT cellular resistance to ionizing radiation
FT without affecting DNA end joining; when
FT associated with A-2638.
FT CONFLICT 405 405 D -> Y (in Ref. 2; AAC50210).
FT CONFLICT 1008 1008 A -> S (in Ref. 2; AAC50210).
FT CONFLICT 3660 3660 N -> T (in Ref. 8; AAA79184).
FT CONFLICT 3817 3817 L -> W (in Ref. 8; AAA79184).
FT CONFLICT 3862 3862 A -> P (in Ref. 8; AAA79184).
FT CONFLICT 4031 4031 I -> V (in Ref. 9; AAK40350).
SQ SEQUENCE 4128 AA; 469089 MW; AC6E747FEB09F3E5 CRC64;
MAGSGAGVRC SLLRLQETLS AADRCGAALA GHQLIRGLGQ ECVLSSSPAV LALQTSLVFS
RDFGLLVFVR KSLNSIEFRE CREEILKFLC IFLEKMGQKI APYSVEIKNT CTSVYTKDRA
AKCKIPALDL LIKLLQTFRS SRLMDEFKIG ELFSKFYGEL ALKKKIPDTV LEKVYELLGL
LGEVHPSEMI NNAENLFRAF LGELKTQMTS AVREPKLPVL AGCLKGLSSL LCNFTKSMEE
DPQTSREIFN FVLKAIRPQI DLKRYAVPSA GLRLFALHAS QFSTCLLDNY VSLFEVLLKW
CAHTNVELKK AALSALESFL KQVSNMVAKN AEMHKNKLQY FMEQFYGIIR NVDSNNKELS
IAIRGYGLFA GPCKVINAKD VDFMYVELIQ RCKQMFLTQT DTGDDRVYQM PSFLQSVASV
LLYLDTVPEV YTPVLEHLVV MQIDSFPQYS PKMQLVCCRA IVKVFLALAA KGPVLRNCIS
TVVHQGLIRI CSKPVVLPKG PESESEDHRA SGEVRTGKWK VPTYKDYVDL FRHLLSSDQM
MDSILADEAF FSVNSSSESL NHLLYDEFVK SVLKIVEKLD LTLEIQTVGE QENGDEAPGV
WMIPTSDPAA NLHPAKPKDF SAFINLVEFC REILPEKQAE FFEPWVYSFS YELILQSTRL
PLISGFYKLL SITVRNAKKI KYFEGVSPKS LKHSPEDPEK YSCFALFVKF GKEVAVKMKQ
YKDELLASCL TFLLSLPHNI IELDVRAYVP ALQMAFKLGL SYTPLAEVGL NALEEWSIYI
DRHVMQPYYK DILPCLDGYL KTSALSDETK NNWEVSALSR AAQKGFNKVV LKHLKKTKNL
SSNEAISLEE IRIRVVQMLG SLGGQINKNL LTVTSSDEMM KSYVAWDREK RLSFAVPFRE
MKPVIFLDVF LPRVTELALT ASDRQTKVAA CELLHSMVMF MLGKATQMPE GGQGAPPMYQ
LYKRTFPVLL RLACDVDQVT RQLYEPLVMQ LIHWFTNNKK FESQDTVALL EAILDGIVDP
VDSTLRDFCG RCIREFLKWS IKQITPQQQE KSPVNTKSLF KRLYSLALHP NAFKRLGASL
AFNNIYREFR EEESLVEQFV FEALVIYMES LALAHADEKS LGTIQQCCDA IDHLCRIIEK
KHVSLNKAKK RRLPRGFPPS ASLCLLDLVK WLLAHCGRPQ TECRHKSIEL FYKFVPLLPG
NRSPNLWLKD VLKEEGVSFL INTFEGGGCG QPSGILAQPT LLYLRGPFSL QATLCWLDLL
LAALECYNTF IGERTVGALQ VLGTEAQSSL LKAVAFFLES IAMHDIIAAE KCFGTGAAGN
RTSPQEGERY NYSKCTVVVR IMEFTTTLLN TSPEGWKLLK KDLCNTHLMR VLVQTLCEPA
SIGFNIGDVQ VMAHLPDVCV NLMKALKMSP YKDILETHLR EKITAQSIEE LCAVNLYGPD
AQVDRSRLAA VVSACKQLHR AGLLHNILPS QSTDLHHSVG TELLSLVYKG IAPGDERQCL
PSLDLSCKQL ASGLLELAFA FGGLCERLVS LLLNPAVLST ASLGSSQGSV IHFSHGEYFY
SLFSETINTE LLKNLDLAVL ELMQSSVDNT KMVSAVLNGM LDQSFRERAN QKHQGLKLAT
TILQHWKKCD SWWAKDSPLE TKMAVLALLA KILQIDSSVS FNTSHGSFPE VFTTYISLLA
DTKLDLHLKG QAVTLLPFFT SLTGGSLEEL RRVLEQLIVA HFPMQSREFP PGTPRFNNYV
DCMKKFLDAL ELSQSPMLLE LMTEVLCREQ QHVMEELFQS SFRRIARRGS CVTQVGLLES
VYEMFRKDDP RLSFTRQSFV DRSLLTLLWH CSLDALREFF STIVVDAIDV LKSRFTKLNE
STFDTQITKK MGYYKILDVM YSRLPKDDVH AKESKINQVF HGSCITEGNE LTKTLIKLCY
DAFTENMAGE NQLLERRRLY HCAAYNCAIS VICCVFNELK FYQGFLFSEK PEKNLLIFEN
LIDLKRRYNF PVEVEVPMER KKKYIEIRKE AREAANGDSD GPSYMSSLSY LADSTLSEEM
SQFDFSTGVQ SYSYSSQDPR PATGRFRRRE QRDPTVHDDV LELEMDELNR HECMAPLTAL
VKHMHRSLGP PQGEEDSVPR DLPSWMKFLH GKLGNPIVPL NIRLFLAKLV INTEEVFRPY
AKHWLSPLLQ LAASENNGGE GIHYMVVEIV ATILSWTGLA TPTGVPKDEV LANRLLNFLM
KHVFHPKRAV FRHNLEIIKT LVECWKDCLS IPYRLIFEKF SGKDPNSKDN SVGIQLLGIV
MANDLPPYDP QCGIQSSEYF QALVNNMSFV RYKEVYAAAA EVLGLILRYV MERKNILEES
LCELVAKQLK QHQNTMEDKF IVCLNKVTKS FPPLADRFMN AVFFLLPKFH GVLKTLCLEV
VLCRVEGMTE LYFQLKSKDF VQVMRHRDDE RQKVCLDIIY KMMPKLKPVE LRELLNPVVE
FVSHPSTTCR EQMYNILMWI HDNYRDPESE TDNDSQEIFK LAKDVLIQGL IDENPGLQLI
IRNFWSHETR LPSNTLDRLL ALNSLYSPKI EVHFLSLATN FLLEMTSMSP DYPNPMFEHP
LSECEFQEYT IDSDWRFRST VLTPMFVETQ ASQGTLQTRT QEGSLSARWP VAGQIRATQQ
QHDFTLTQTA DGRSSFDWLT GSSTDPLVDH TSPSSDSLLF AHKRSERLQR APLKSVGPDF
GKKRLGLPGD EVDNKVKGAA GRTDLLRLRR RFMRDQEKLS LMYARKGVAE QKREKEIKSE
LKMKQDAQVV LYRSYRHGDL PDIQIKHSSL ITPLQAVAQR DPIIAKQLFS SLFSGILKEM
DKFKTLSEKN NITQKLLQDF NRFLNTTFSF FPPFVSCIQD ISCQHAALLS LDPAAVSAGC
LASLQQPVGI RLLEEALLRL LPAELPAKRV RGKARLPPDV LRWVELAKLY RSIGEYDVLR
GIFTSEIGTK QITQSALLAE ARSDYSEAAK QYDEALNKQD WVDGEPTEAE KDFWELASLD
CYNHLAEWKS LEYCSTASID SENPPDLNKI WSEPFYQETY LPYMIRSKLK LLLQGEADQS
LLTFIDKAMH GELQKAILEL HYSQELSLLY LLQDDVDRAK YYIQNGIQSF MQNYSSIDVL
LHQSRLTKLQ SVQALTEIQE FISFISKQGN LSSQVPLKRL LNTWTNRYPD AKMDPMNIWD
DIITNRCFFL SKIEEKLTPL PEDNSMNVDQ DGDPSDRMEV QEQEEDISSL IRSCKFSMKM
KMIDSARKQN NFSLAMKLLK ELHKESKTRD DWLVSWVQSY CRLSHCRSRS QGCSEQVLTV
LKTVSLLDEN NVSSYLSKNI LAFRDQNILL GTTYRIIANA LSSEPACLAE IEEDKARRIL
ELSGSSSEDS EKVIAGLYQR AFQHLSEAVQ AAEEEAQPPS WSCGPAAGVI DAYMTLADFC
DQQLRKEEEN ASVIDSAELQ AYPALVVEKM LKALKLNSNE ARLKFPRLLQ IIERYPEETL
SLMTKEISSV PCWQFISWIS HMVALLDKDQ AVAVQHSVEE ITDNYPQAIV YPFIISSESY
SFKDTSTGHK NKEFVARIKS KLDQGGVIQD FINALDQLSN PELLFKDWSN DVRAELAKTP
VNKKNIEKMY ERMYAALGDP KAPGLGAFRR KFIQTFGKEF DKHFGKGGSK LLRMKLSDFN
DITNMLLLKM NKDSKPPGNL KECSPWMSDF KVEFLRNELE IPGQYDGRGK PLPEYHVRIA
GFDERVTVMA SLRRPKRIII RGHDEREHPF LVKGGEDLRQ DQRVEQLFQV MNGILAQDSA
CSQRALQLRT YSVVPMTSRL GLIEWLENTV TLKDLLLNTM SQEEKAAYLS DPRAPPCEYK
DWLTKMSGKH DVGAYMLMYK GANRTETVTS FRKRESKVPA DLLKRAFVRM STSPEAFLAL
RSHFASSHAL ICISHWILGI GDRHLNNFMV AMETGGVIGI DFGHAFGSAT QFLPVPELMP
FRLTRQFINL MLPMKETGLM YSIMVHALRA FRSDPGLLTN TMDVFVKEPS FDWKNFEQKM
LKKGGSWIQE INVAEKNWYP RQKICYAKRK LAGANPAVIT CDELLLGHEK APAFRDYVAV
ARGSKDHNIR AQEPESGLSE ETQVKCLMDQ ATDPNILGRT WEGWEPWM
//

MIM 600899
*RECORD*
*FIELD* NO
600899
*FIELD* TI
*600899 PROTEIN KINASE, DNA-ACTIVATED, CATALYTIC SUBUNIT; PRKDC
;;DNA-DEPENDENT PROTEIN KINASE, CATALYTIC SUBUNIT; DNPK1;;
read morep350;;
DNA-PKcs;;
DNA-DEPENDENT PROTEIN KINASE; DNAPK;;
HYPERRADIOSENSITIVITY COMPLEMENTING 1, MOUSE, HOMOLOG OF; HYRC1
*FIELD* TX

DESCRIPTION

The PRKDC gene encodes the catalytic subunit of a nuclear DNA-dependent
serine/threonine protein kinase (DNA-PK). The second component is the
autoimmune antigen Ku (152690), which is encoded by the G22P1 gene on
chromosome 22q. On its own, the catalytic subunit of DNA-PK is inactive
and relies on the G22P1 component to direct it to the DNA and trigger
its kinase activity; PRKDC must be bound to DNA to express its catalytic
properties.

CLONING

Sipley et al. (1995) reported a partial sequence of the PRKDC gene.

Hartley et al. (1995) isolated a PRKDC cDNA, which encodes a 4,096-amino
acid protein with a molecular mass of 360 kD. The PRKDC protein showed
similarity to phosphatidylinositol 3-kinase family members involved in
cell cycle control, DNA repair, and DNA damage responses, and had no
detectable activity towards lipids. Other PI kinase proteins involved in
DNA repair include FKBP12 (186945) and the ataxia-telangiectasia gene
(ATM; 607585), in which mutations lead to genomic instability and
predisposition to cancer and ataxia.

Independently, Poltoratsky et al. (1995) cloned and sequenced a cDNA
encoding the C-terminal 931 amino acids of PRKDC. They showed that this
region has homology to phosphatidylinositol kinases.

GENE STRUCTURE

Sipley et al. (1995) reported that the PRKDC gene contains 9 exons.

MAPPING

By fluorescence in situ hybridization (FISH), Sipley et al. (1995)
mapped the PRKDC gene to chromosome 8q11, coincident with XRCC7 (HYRC1),
a human homolog of a gene that complements the DNA double-strand break
repair and V(D)J recombination defects of hamster V3 and murine severe
combined immunodeficient (scid) cells (see GENE FUNCTION).

Ladenburger et al. (1997) showed that the 5-prime ends of the PRKDC and
MCM4 (602638) genes are less than 1 kb apart on 8q12-q13. These genes
are transcribed in opposite directions and have autonomous promoters.
Satoh et al. (1997) mapped the MCM4 gene to 8q11.2 by FISH. Based on the
close proximity of the PRKDC and MCM4 genes, it was assumed that the
PRKDC gene also maps to this location. Connelly et al. (1998) reported
that the transcription initiation sites of the PRKDC and MCM4 genes are
separated by approximately 700 bp, and the start codons by 1,018 bp.

The mouse Prkdc gene is located on chromosome 16 (see ANIMAL MODEL and
Bosma et al., 1989, Miller et al., 1993, and Komatsu et al., 1993).

GENE FUNCTION

Anderson and Lees-Miller (1992) noted that DNA-PK had been shown in
vitro to phosphorylate several transcription factors, suggesting that it
functions in cell homeostasis by modulating transcription. DNA-PK
activation requires Ku-binding to DNA double-stranded breaks or other
discontinuities in the DNA double helix, suggesting that DNA-PK
recognizes DNA ends at sites of DNA damage or that occur as
recombination intermediates. Cells defective in DNA-PK components are
hypersensitive to killing by ionizing radiation due to an inability to
repair double-stranded breaks effectively. Cells defective in either Ku
or DNA-PK catalytic subunit are also unable to perform V(D)J
recombination, the site-specific recombination process that takes place
in developing B and T lymphocytes to generate variable regions of
immunoglobulin and T cell receptor genes. In the absence of DNA-PK
function, V(D)J recombination intermediates are unable to be processed
and ligated (Hartley et al., 1995).

Kuhn et al. (1995) and Labhart (1995) reported that DNA-PK suppressed
RNA polymerase I transcription in both mouse and purified Xenopus cell
extract, respectively, but did not inhibit transcription by RNA
polymerases II or III (Labhart, 1995).

Lees-Miller et al. (1995) showed that the radiosensitive human malignant
glioma M059J cell line is defective in DNA double-strand break repair
and fails to express the p350 subunit of DNA-PK.

Shieh et al. (1997) demonstrated that p53 (191170) was phosphorylated at
ser15 and ser37 by purified DNA-PK, and that this modification impaired
the ability of MDM2 (164785) to inhibit p53-dependent transactivation.
They presented evidence that these effects were most likely due to a
conformational change induced by phosphorylation of p53.

Daniel et al. (1999) demonstrated that the PRKDC protein participates in
retroviral DNA integration, which is catalyzed by the viral protein
integrase. Prkdc-deficient murine scid cells infected with 3 different
retroviruses showed a substantial reduction in retroviral DNA
integration and died by apoptosis. Scid cell killing was not observed
after infection with an integrase-defective virus, suggesting that
abortive integration is the trigger for death in these DNA
repair-deficient cells. These results suggested that the initial events
in retroviral integration are detected as DNA damage by the host cell,
and that completion of the integration process requires the
DNA-PK-mediated repair pathway.

Jimenez et al. (1999) demonstrated that the p53 response was fully
functional in primary mouse embryonic fibroblasts lacking Prkdc:
irradiation-induced DNA damage in these defective fibroblasts induced a
normal response of p53 accumulation, phosphorylation of p53 serine
residue at position 15, nuclear localization, and binding to DNA of p53.
Jimenez et al. (1999) also reported that the Prkdc-deficient cell line
contained a homozygous mutation in the DNA-binding domain of p53, which
may explain the defective response by p53 reported in this line by Woo
et al. (1998). Jimenez et al. (1999) concluded that DNA-PK activity was
not required for cells to mount a p53-dependent response to DNA damage.

In mammalian cells, abrogation of telomeric repeat-binding factor TRF2
(TERF2; 602027) or DNA-PK activity causes end-to-end chromosomal fusion,
establishing a central role for these proteins in telomere function.
Bailey et al. (2001) demonstrated that TRF2-mediated end-capping
occurred after telomere replication. The postreplicative requirement for
TRF2 and DNA-PK catalytic subunit was confined to only the half of the
telomeres that were produced by leading-strand DNA synthesis. Bailey et
al. (2001) concluded that there was a crucial difference in
postreplicative processing of telomeres that was linked to their mode of
replication.

Ma et al. (2002) determined that the Artemis protein (605988) formed a
complex with PRKDC in the absence of DNA. The purified Artemis protein
alone possessed single-strand-specific 5-prime-to-3-prime exonuclease
activity. Upon complex formation, PRKDC phosphorylated Artemis, and
Artemis acquired endonucleolytic activity on 5-prime and 3-prime
overhangs, as well as hairpins. The Artemis-PRKDC complex can open
hairpins generated by the RAG (see 179615) complex. Ma et al. (2002)
concluded that PRKDC 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-prime and
3-prime overhang processing in nonhomologous DNA end joining.

Falck et al. (2005) identified related, conserved C-terminal motifs in
human NBS1 (602667), ATRIP (606605), and Ku80 (194364) proteins that are
required for their interaction with members of the phosphoinositide
3-kinase-related protein kinase (PIKK; see 607032) family, ATM (607585),
ATR (601215), and DNA-PKcs, respectively. These EEXXXDDL motifs are
essential not only for efficient recruitment of ATM, ATR, and DNA-PKcs
to sites of damage, but are also critical for ATM-, ATR-, and
DNA-PKcs-mediated signaling events that trigger cell cycle checkpoints
and DNA repair. Falck et al. (2005) concluded that recruitment of these
PIKKs to DNA lesions occurs by common mechanisms through an
evolutionarily conserved motif, and provide direct evidence that PIKK
recruitment is required for PIKK-dependent DNA-damage signaling.

Soutoglou and Misteli (2008) demonstrated that prolonged binding of DNA
repair factors to chromatin can elicit the DNA damage response in an
ATM- and DNAPK-dependent manner in the absence of DNA damage. Targeting
of single repair factors to chromatin revealed a hierarchy of protein
interactions within the repair complex and suggested amplification of
the damage signal. Soutoglou and Misteli (2008) concluded that
activation of the DNA damage response does not require DNA damage, and
stable association of repair factors with chromatin is likely a critical
step in triggering, amplifying, and maintaining the DNA damage repair
signal.

Lu et al. (2008) reported that the kinase activity of the Artemis:PRKDC
complex could be activated by hairpin DNA ends in cis, allowing nicking
of hairpins, followed by processing and joining by nonhomologous DNA end
joining. These insights enabled reconstitution of many aspects of
antigen receptor diversification of V(D)J recombination using 13 highly
purified polypeptides, thereby permitting variable domain exon assembly.
The features of the recombination sites created by this biochemical
system included all of the features observed in vivo, such as
nucleolytic resection, P nucleotides, and N nucleotide addition, and
indicated that most, if not all, of the end modification enzymes had
been identified.

ANIMAL MODEL

Bosma et al. (1983) reported homozygous mice with features of severe
combined immunodeficiency (scid), including lymphopenia,
hypogammaglobulinemia, and impaired immune functions mediated by T and B
lymphocytes. Hendrickson et al. (1988) determined that the defect in the
scid mouse resides in the gene for a transacting factor that mediates
the rejoining event for rearrangement of the immunoglobulin gene;
heavy-chain gene rearrangement was found to be blocked at the D-J stage.

By linkage of scid to mahoganoid (md), a recessive mouse coat color
marker on chromosome 16, Bosma et al. (1989) determined that autosomal
recessive murine scid maps to the centromeric end of chromosome 16.
Miller et al. (1993) constructed a refined linkage map of the
centromeric region of mouse chromosome 16, placing the scid gene between
Prm2 (182890) and Igl1. No recombination was found between scid and the
VpreB and lambda-5 genes which are specific to developmental stages of B
cells.

Komatsu et al. (1993) introduced fragments of human chromosome 8 into
cells derived from scid mice by X-irradiation and somatic cell fusion.
The resulting hybrid clones contained human DNA fragments that
complemented the hyperradiosensitivity of the scid cells. Alu-PCR
products from these hybrids were used for chromosome painting by the
technique of chromosome in situ suppression hybridization, allowing
assignment of the human homolog of the mouse scid locus, HYRC1
(hyperradiosensitivity complementing-1), to human chromosome 8q11. Using
the same microcell technique, Kurimasa et al. (1994) demonstrated
correction of radiation sensitivity by a fragment of human chromosome 8
representing 8p11.1-q11.1. Using similar methods, Komatsu et al. (1995)
demonstrated that the scid cells were also fully complemented for the
V(D)J recombination reaction, whereas the uncomplemented control cells
failed to carry out V(D)J recombination normally. The findings indicated
that the HYRC1 locus encodes the SCID factor involved in all V(D)J
recombination coding joint formation and in 30 to 35% of repair of
double-strand breaks.

Kirchgessner et al. (1995) identified PRKDC as a strong candidate for
the human homolog of the mouse scid gene. Chromosomal fragments
expressing PRKDC complemented the scid phenotype, and PRKDC protein
levels were greatly reduced in cells derived from scid mice compared to
cells from wildtype mice. The authors established the existence of a new
synteny group between human chromosome 8q11, containing the p350 gene
and the CEBPD gene (116898), and the centromeric region of mouse
chromosome 16 at the position of the scid locus.

Miller et al. (1995) used a partial cDNA clone for human PRKDC to map
the mouse homolog using a large interspecific backcross panel. They
found that the mouse gene did not recombine with scid, consistent with
the hypothesis that scid results from a mutation in the mouse Prkdc
gene.

In 4 individual scid mice, Araki et al. (1997) demonstrated a T-to-A
transversion in codon tyr4406 of the Prkdc gene, resulting in a nonsense
mutation and a truncated protein missing 83 amino acids. The mutation
was in the phosphatidylinositol 3-kinase domain of the protein. The same
mutation was found in the scid mouse by Blunt et al. (1996) and Danska
et al. (1996).

Hendrickson (1993) reviewed the relevance of the scid mouse as an animal
model system for studying human disease.

SCID in Arabian foals is an autosomal recessive mutation that results in
primary immunodeficiency. Wiler et al. (1995) showed that SCID in
Arabian horses is almost precisely analogous to that found in mice. The
horses had severely depressed numbers of both B and T lymphocytes,
whereas natural killer cell activity was normal. In studies of the
equine disorder, Wiler et al. (1995) showed that the factor defective is
required for V(D)J recombination, resistance to ionizing radiation, and
DNA-dependent protein kinase activity. The authors concluded that the
Prkdc gene is defective in both mice and Arabian foals with scid.

*FIELD* RF
1. Anderson, C. W.; Lees-Miller, S. P.: The nuclear serine/threonine
protein kinase DNA-PK. Crit. Rev. Eukaryot. Gene Expr. 2: 283-314,
1992.

2. Araki, R.; Fujimori, A.; Hamatani, K.; Mita, K.; Saito, T.; Mori,
M.; Fukumura, R.; Morimyo, M.; Muto, M.; Itoh, M.; Tatsumi, K.; Abe,
M.: Nonsense mutation at tyr-4046 in the DNA-dependent protein kinase
catalytic subunit of severe combined immune deficiency mice. Proc.
Nat. Acad. Sci. 94: 2438-2443, 1997.

3. Bailey, S. M.; Cornforth, M. N.; Kurimasa, A.; Chen, D. J.; Goodwin,
E. H.: Strand-specific postreplicative processing of mammalian telomeres. Science 293:
2462-2465, 2001.

4. Blunt, T.; Gell, D.; Fox, M.; Taccioli, G. E.; Lehmann, A. R.;
Jackson, S. P.; Jeggo, P. A.: Identification of a nonsense mutation
in the carboxyl-terminal region of DNA-dependent protein kinase catalytic
subunit in the scid mouse. Proc. Nat. Acad. Sci. 93: 10285-10290,
1996.

5. Bosma, G. C.; Custer, R. P.; Bosma, M. J.: A severe combined immunodeficiency
mutation in the mouse. Nature 301: 527-530, 1983.

6. Bosma, G. C.; Davisson, M. T.; Ruetsch, N. R.; Sweet, H. O.; Shultz,
L. D.; Bosma, M. J.: The mouse mutation severe combined immune deficiency
(scid) is on chromosome 16. Immunogenetics 29: 54-57, 1989. Note:
Erratum: Immunogenetics 29: 224 only, 1989.

7. Connelly, M. A.; Zhang, H.; Kieleczawa, J.; Anderson, C. W.: The
promoters for human DNA-PK(cs) (PRKDC) and MCM4: divergently transcribed
genes located at chromosome 8 band q11. Genomics 47: 71-83, 1998.

8. Daniel, R.; Katz, R. A.; Skalka, A. M.: A role for DNA-PK in retroviral
DNA integration. Science 284: 644-647, 1999.

9. Danska, J. S.; Holland, D. P.; Mariathasan, S.; Williams, K. M.;
Guidos, C. J.: Biochemical and genetic defects in the DNA-dependent
protein kinase in murine scid lymphocytes. Molec. Cell. Biol. 16:
5507-5517, 1996.

10. Falck, J.; Coates, J.; Jackson, S. P.: Conserved modes of recruitment
of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434: 605-611,
2005.

11. 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.;
Jackson, S. P.: DNA-dependent protein kinase catalytic subunit: a
relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia
gene product. Cell 82: 849-856, 1995.

12. Hendrickson, E. A.: The scid mouse: relevance as an animal model
system for studying human disease. Am. J. Path. 143: 1511-1522,
1993.

13. Hendrickson, E. A.; Schatz, D. G.; Weaver, D. T.: The scid gene
encodes a trans-acting factor that mediates the rejoining event of
Ig gene rearrangement. Genes Dev. 2: 817-829, 1988.

14. Jimenez, G. S.; Bryntesson, F.; Torres-Arzayus, M. I.; Priestley,
A.; Beeche, M.; Saito, S.; Sakaguchi, K.; Appella, E.; Jeggo, P. A.;
Taccioli, G. E.; Wahl, G. M.; Hubank, M.: DNA-dependent protein kinase
is not required for the p53-dependent response to DNA damage. Nature 400:
81-83, 1999.

15. 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 267:
1178-1183, 1995.

16. Komatsu, K.; Kubota, N.; Gallo, M.; Okumura, Y.; Lieber, M. R.
: The scid factor on human chromosome 8 restores V(D)J recombination
in addition to double-strand break repair. Cancer Res. 55: 1774-1779,
1995.

17. Komatsu, K.; Ohta, T.; Jinno, Y.; Niikawa, N.; Okumura, Y.: Functional
complementation in mouse-human radiation hybrids assigns the putative
murine scid gene to the pericentric region of human chromosome 8. Hum.
Molec. Genet. 2: 1031-1034, 1993.

18. 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. 9: 193-203, 1995.

19. Kurimasa, A.; Nagata, Y.; Shimizu, M.; Emi, M.; Nakamura, Y.;
Oshimura, M.: A human gene that restores the DNA-repair defect in
Scid mice is located on 8p11.1-q11.1. Hum. Genet. 93: 21-26, 1994.

20. Labhart, P.: DNA-dependent protein kinase specifically represses
promoter-directed transcription initiation by RNA polymerase I. Proc.
Nat. Acad. Sci. 92: 2934-2938, 1995.

21. Ladenburger, E. M.; Fackelmayer, F. O.; Hameister, H.; Knippers,
R.: MCM4 and PRKDC, human genes encoding proteins MCM4 and DNA-PKcs,
are close neighbours located on chromosome 8q12-q13. Cytogenet. Cell
Genet. 77: 268-270, 1997.

22. Lees-Miller, S. P.; Godbout, R.; Chan, D. W.; Weinfeld, M.; Day,
R. S., III; Barron, G. M.; Allalunis-Turner, J.: Absence of p350
subunit of DNA-activated protein kinase from a radiosensitive human
cell line. Science 267: 1183-1185, 1995.

23. Lu, H.; Shimazaki, N.; Raval, P.; Gu, J.; Watanabe, G.; Schwarz,
K.; Swanson, P. C.; Lieber, M. R.: A biochemically defined system
for coding joint formation in V(D)J recombination. Molec. Cell 31:
485-497, 2008.

24. Ma, Y.; Pannicke, U.; Schwarz, K.; Lieber, M. R.: Hairpin opening
and overhang processing by an Artemis/DNA-dependent protein kinase
complex in nonhomologous end joining and V(D)J recombination. Cell 108:
781-794, 2002.

25. Miller, R. D.; Hogg, J.; Ozaki, J. H.; Gell, D.; Jackson, S. P.;
Riblet, R.: Gene for catalytic subunit of mouse DNA-dependent protein
kinase maps to the scid locus. Proc. Nat. Acad. Sci. 92: 10792-10795,
1995.

26. Miller, R. D.; Ozaki, J. H.; Riblet, R.: The mouse severe combined
immune deficiency (scid) mutation is closely linked to the B-cell-specific
developmental genes VpreB and lambda-5. Genomics 16: 740-744, 1993.

27. Poltoratsky, V. P.; Shi, X.; York, J. D.; Lieber, M. R.; Carter,
T. H.: Human DNA-activated protein kinase (DNA-PK) is homologous
to phosphatidylinositol kinases. J. Immun. 155: 4529-4533, 1995.

28. Satoh, T.; Tsuruga, H.; Yabuta, N.; Ishidate, M., Jr.; Nojima,
H.: Assignment of the human CDC21 (MCM4) gene to chromosome 8q11.2. Genomics 46:
525-526, 1997.

29. Shieh, S.-Y.; Ikeda, M.; Taya, Y.; Prives, C.: DNA damage-induced
phosphorylation of p53 alleviates inhibition by MDM2. Cell 91: 325-334,
1997.

30. Sipley, J. D.; Menninger, J. C.; Hartley, K. O.; Ward, D. C.;
Jackson, S. P.; Anderson, C. W.: Gene for the catalytic subunit of
the human DNA-activated protein kinase maps to the site of the XRCC7
gene on chromosome 8. Proc. Nat. Acad. Sci. 92: 7515-7519, 1995.

31. Soutoglou, E.; Misteli, T.: Activation of the cellular DNA damage
response in the absence of DNA lesions. Science 320: 1507-1510,
2008. Note: Erratum: Science 327: 959 only, 2010.

32. Wiler, R.; Leber, R.; Moore, B. B.; VanDyk, L. F.; Perryman, L.
E.; Meek, K.: Equine severe combined immunodeficiency: A defect in
V(D)J recombination and DNA-dependent protein kinase activity. Proc.
Nat. Acad. Sci. 92: 11485-11489, 1995.

33. Woo, R. A.; McLure, K. G.; Lees-Miller, S. P.; Rancourt, D. E.;
Lee, P. W.: DNA-dependent protein kinase acts upstream of p53 in
response to DNA damage. Nature 394: 700-704, 1998.

*FIELD* CN
Ada Hamosh - updated: 3/9/2010
Paul J. Converse - updated: 2/13/2009
Ada Hamosh - updated: 7/11/2008
Ada Hamosh - updated: 5/25/2005
Cassandra L. Kniffin - reorganized: 10/28/2004
Stylianos E. Antonarakis - updated: 5/6/2002
Ada Hamosh - updated: 10/9/2001
Ada Hamosh - updated: 8/24/1999
Ada Hamosh - updated: 5/7/1999
Rebekah S. Rasooly - updated: 5/20/1998
Stylianos E. Antonarakis - updated: 12/4/1997
Victor A. McKusick - edited: 7/9/1997
Victor A. McKusick - updated: 4/21/1997

*FIELD* CD
Victor A. McKusick: 11/1/1995

*FIELD* ED
terry: 08/08/2012
terry: 3/9/2010
mgross: 2/13/2009
alopez: 7/15/2008
terry: 7/11/2008
wwang: 5/27/2005
wwang: 5/25/2005
terry: 5/25/2005
carol: 10/28/2004
ckniffin: 10/20/2004
alopez: 11/20/2003
ckniffin: 3/11/2003
mgross: 5/6/2002
terry: 12/7/2001
alopez: 10/11/2001
terry: 10/9/2001
mcapotos: 12/7/1999
alopez: 8/31/1999
terry: 8/24/1999
alopez: 5/7/1999
terry: 5/7/1999
dkim: 12/3/1998
dkim: 7/30/1998
psherman: 5/20/1998
carol: 12/5/1997
carol: 12/4/1997
mark: 7/9/1997
terry: 7/9/1997
alopez: 6/27/1997
jenny: 4/21/1997
terry: 4/11/1997
terry: 1/17/1997
mark: 1/14/1996
joanna: 1/7/1996
mark: 12/6/1995
terry: 11/6/1995
mark: 11/1/1995