Description: Homo sapiens protein kinase, DNA-activated, catalytic polypeptide (PRKDC), transcript variant 1, mRNA. RefSeq Summary (NM_006904): This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK). It functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. The protein encoded is a member of the PI3/PI4-kinase family.[provided by RefSeq, Jul 2010]. Transcript (Including UTRs) Position: hg19 chr8:48,685,669-48,872,743 Size: 187,075 Total Exon Count: 87 Strand: - Coding Region Position: hg19 chr8:48,686,734-48,872,686 Size: 185,953 Coding Exon Count: 87
ID:PRKDC_HUMAN DESCRIPTION: RecName: Full=DNA-dependent protein kinase catalytic subunit; Short=DNA-PK catalytic subunit; Short=DNA-PKcs; EC=2.7.11.1; AltName: Full=DNPK1; AltName: Full=p460; FUNCTION: Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA nonhomologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Required to protect and align broken ends of DNA. May also act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. Also involved in modulation of transcription. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX, thereby regulating DNA damage response mechanism. Phosphorylates DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, SRF, XRCC1, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Inhibited by wortmannin. Activity of the enzyme seems to be attenuated by autophosphorylation. SUBUNIT: DNA-PK is a heterotrimer of PRKDC and the Ku p70-p86 (XRCC6-XRCC5) dimer. Formation of this complex may be promoted by interaction with ILF3. Associates with the DNA-bound Ku heterodimer, but it can also bind to and be activated by free DNA. Interacts with DNA-PKcs-interacting protein (KIP) with the region upstream the kinase domain. PRKDC alone also interacts with and phosphorylates DCLRE1C, thereby activating the latent endonuclease activity of this protein. Interacts with C1D. Interacts with TTI1 and TELO2. INTERACTION: O43918:AIRE; NbExp=2; IntAct=EBI-352053, EBI-1753081; P42575:CASP2; NbExp=4; IntAct=EBI-352053, EBI-520342; P14921:ETS1; NbExp=2; IntAct=EBI-352053, EBI-913209; P50549:ETV1; NbExp=2; IntAct=EBI-352053, EBI-3905068; P09629:HOXB7; NbExp=2; IntAct=EBI-352053, EBI-1248457; Q9HB75:PIDD; NbExp=6; IntAct=EBI-352053, EBI-520427; P17947:SPI1; NbExp=2; IntAct=EBI-352053, EBI-2293548; P13010:XRCC5; NbExp=6; IntAct=EBI-352053, EBI-357997; P12956:XRCC6; NbExp=5; IntAct=EBI-352053, EBI-353208; P25490:YY1; NbExp=2; IntAct=EBI-352053, EBI-765538; SUBCELLULAR LOCATION: Nucleus. Nucleus, nucleolus. PTM: Phosphorylated upon DNA damage, probably by ATM or ATR. Autophosphorylated on Thr-2609, Thr-2638 and Thr-2647. Thr-2609 is a DNA damage-inducible phosphorylation site (inducible with ionizing radiation, IR). Autophosphorylation induces a conformational change that leads to remodeling of the DNA-PK complex, requisite for efficient end processing and DNA repair. PTM: S-nitrosylated by GAPDH (By similarity). SIMILARITY: Belongs to the PI3/PI4-kinase family. SIMILARITY: Contains 1 FAT domain. SIMILARITY: Contains 1 FATC domain. SIMILARITY: Contains 2 HEAT repeats. SIMILARITY: Contains 1 PI3K/PI4K domain. SIMILARITY: Contains 3 TPR repeats. WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/prkdc/";
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Genetic Association Studies of Complex Diseases and Disorders
Genetic Association Database (archive): PRKDC CDC HuGE Published Literature: PRKDC Positive Disease Associations: Body Weight
, Breath Tests Related Studies:
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
SCOP Domains: 48371 - ARM repeat 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on P78527
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000723 telomere maintenance GO:0001756 somitogenesis GO:0001933 negative regulation of protein phosphorylation GO:0002218 activation of innate immune response GO:0002326 B cell lineage commitment GO:0002328 pro-B cell differentiation GO:0002360 T cell lineage commitment GO:0002376 immune system process GO:0002377 immunoglobulin production GO:0002638 negative regulation of immunoglobulin production GO:0002684 positive regulation of immune system process GO:0006281 DNA repair GO:0006302 double-strand break repair GO:0006303 double-strand break repair via nonhomologous end joining GO:0006310 DNA recombination GO:0006464 cellular protein modification process GO:0006468 protein phosphorylation GO:0006974 cellular response to DNA damage stimulus GO:0007420 brain development GO:0007507 heart development GO:0008283 cell proliferation GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage GO:0010212 response to ionizing radiation GO:0010332 response to gamma radiation GO:0014823 response to activity GO:0016233 telomere capping GO:0016310 phosphorylation GO:0016567 protein ubiquitination GO:0018105 peptidyl-serine phosphorylation GO:0030098 lymphocyte differentiation GO:0031648 protein destabilization GO:0032481 positive regulation of type I interferon production GO:0032869 cellular response to insulin stimulus GO:0033077 T cell differentiation in thymus GO:0033151 V(D)J recombination GO:0033152 immunoglobulin V(D)J recombination GO:0033153 T cell receptor V(D)J recombination GO:0035234 ectopic germ cell programmed cell death GO:0042752 regulation of circadian rhythm GO:0043065 positive regulation of apoptotic process GO:0043066 negative regulation of apoptotic process GO:0045087 innate immune response GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0048146 positive regulation of fibroblast proliferation GO:0048511 rhythmic process GO:0048536 spleen development GO:0048538 thymus development GO:0048639 positive regulation of developmental growth GO:0048660 regulation of smooth muscle cell proliferation GO:0072431 signal transduction involved in mitotic G1 DNA damage checkpoint GO:0097681 double-strand break repair via alternative nonhomologous end joining GO:2000773 negative regulation of cellular senescence GO:2001229 negative regulation of response to gamma radiation
U47077 - Homo sapiens DNA-dependent protein kinase catalytic subunit (DNA-PKcs) mRNA, complete cds. AK296833 - Homo sapiens cDNA FLJ57825 complete cds, highly similar to DNA-dependent protein kinase catalytic subunit (EC 2.7.11.1). U34994 - Homo sapiens DNA dependent protein kinase catalytic subunit (PRKDC) mRNA, complete cds; alternatively spliced. BC024963 - Homo sapiens, clone IMAGE:2900772, mRNA. BC037968 - Homo sapiens, Similar to protein kinase, DNA-activated, catalytic polypeptide, clone IMAGE:4508982, mRNA. BC017494 - Homo sapiens protein kinase, DNA-activated, catalytic polypeptide, mRNA (cDNA clone IMAGE:3921127), with apparent retained intron. AB208860 - Homo sapiens mRNA for protein kinase, DNA-activated, catalytic polypeptide variant protein. JD375258 - Sequence 356282 from Patent EP1572962. JD038413 - Sequence 19437 from Patent EP1572962. JD358736 - Sequence 339760 from Patent EP1572962. JD072632 - Sequence 53656 from Patent EP1572962. JD350264 - Sequence 331288 from Patent EP1572962. JD357043 - Sequence 338067 from Patent EP1572962. U35835 - Human DNA-PK mRNA, partial cds. JD267038 - Sequence 248062 from Patent EP1572962. AK022387 - Homo sapiens cDNA FLJ12325 fis, clone MAMMA1002125.
Biochemical and Signaling Pathways
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa03450 - Non-homologous end-joining hsa04110 - Cell cycle
BioCarta from NCI Cancer Genome Anatomy Project h_fasPathway - FAS signaling pathway ( CD95 ) h_g2Pathway - Cell Cycle: G2/M Checkpoint h_tnfr1Pathway - TNFR1 Signaling Pathway h_HivnefPathway - HIV-I Nef: negative effector of Fas and TNF
Reactome (by CSHL, EBI, and GO)
Protein P78527 (Reactome details) participates in the following event(s):
R-HSA-5693615 Association of DNA-PKcs with Ku-bound ends of DNA double-strand breaks - synapsis R-HSA-5693604 XRCC4:LIG4 ligates DNA DSB ends during NHEJ R-HSA-3134821 DNA-PK binds microbial dsDNA R-HSA-8938770 RNF144A binds PRKDC and Ubiquitin:UBE2L3 R-HSA-5693575 DNA-PKcs autophosphorylates R-HSA-5686924 DCLRE1C binds PRKDC:XRCC5:XRCC6 at DNA DSBs R-HSA-5693574 XRCC4:LIG4, NHEJ1 and POLL or POLM bind DNA DSBs in NHEJ R-HSA-5693578 TDP1 and TDP2 process unligatable DSB ends R-HSA-5687360 POLL or POLM extends aligned DNA DSB ends to fill gaps R-HSA-5693533 DCLRE1C (ARTEMIS) processes DNA DSB ends R-HSA-5687183 PRKDC phosphorylates DCLRE1C at DNA DSBs R-HSA-5693571 Nonhomologous End-Joining (NHEJ) R-HSA-1834949 Cytosolic sensors of pathogen-associated DNA R-HSA-8866654 E3 ubiquitin ligases ubiquitinate target proteins R-HSA-5693532 DNA Double-Strand Break Repair R-HSA-168249 Innate Immune System R-HSA-8852135 Protein ubiquitination R-HSA-73894 DNA Repair R-HSA-168256 Immune System R-HSA-597592 Post-translational protein modification R-HSA-392499 Metabolism of proteins
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