DNA-PKcs

Protein kinase, DNA-activated, catalytic polypeptide
Identifiers
Symbols	PRKDC; DNA-PKcs; DNAPK; DNPK1; HYRC; HYRC1; XRCC7; p350
External IDs	OMIM: 600899 MGI: 104779 HomoloGene: 5037 GeneCards: PRKDC Gene
EC number	2.7.11.1
Gene Ontology Molecular function • nucleotide binding • DNA binding • protein kinase activity • protein serine/threonine kinase activity • DNA-dependent protein kinase activity • protein binding • ATP binding • transcription factor binding • kinase activity • enzyme binding Cellular component • nucleus • nucleoplasm • nucleoplasm • transcription factor complex • DNA-dependent protein kinase-DNA ligase 4 complex • nonhomologous end joining complex Biological process • telomere maintenance • somitogenesis • B cell lineage commitment • pro-B cell differentiation • T cell lineage commitment • DNA repair • double-strand break repair • double-strand break repair via nonhomologous end joining • DNA recombination • protein modification process • protein phosphorylation • brain development • heart development • response to gamma radiation • phosphorylation • peptidyl-serine phosphorylation • lymphocyte differentiation • protein destabilization • cellular response to insulin stimulus • T cell differentiation in thymus • immunoglobulin V(D)J recombination • T cell receptor V(D)J recombination • germ cell programmed cell death • positive regulation of apoptosis • positive regulation of transcription from RNA polymerase II promoter Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5591	19090
Ensembl	ENSG00000253729	ENSMUSG00000022672
UniProt	P78527	Q91UZ3
RefSeq (mRNA)	NM_001081640.1	NM_011159.2
RefSeq (protein)	NP_001075109.1	NP_035289.2
Location (UCSC)	Chr 8: 48.69 – 48.87 Mb	Chr 16: 15.64 – 15.84 Mb
PubMed search	[1]	[2]

DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the PRKDC gene.^[1] DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family.

Function

DNA-PKcs is the catalytic subunit of a nuclear DNA-dependent serine/threonine protein kinase called DNA-PK. The second component is the autoimmune antigen Ku. On its own, DNA-PKcs is inactive and relies on Ku to direct it to DNA ends and trigger its kinase activity^[2] DNA-PKcs is required for the non-homologous end joining (NHEJ) pathway of DNA repair, which rejoins double-strand breaks. It is also required for V(D)J recombination, a process that utilizes NHEJ to promote immune system diversity. DNA-PKcs knockout mice have severe combined immunodeficiency due to their V(D)J recombination defect.

Many proteins have been identified as substrates for the kinase activity of DNA-PK. Autophosphorylation of DNA-PKcs appears to play a key role in NHEJ and is thought to induce a conformational change that allows end processing enzymes to access the ends of the double-strand break.^[3] DNA-PK also cooperates with ATR and ATM to phosphorylate proteins involved in the DNA damage checkpoint.

Interactions

DNA-PKcs has been shown to interact with NCOA6,^[4] CHEK1,^[5][6] Werner syndrome ATP-dependent helicase,^[5][7] RPA2,^[8] ILF3,^[9] DCLRE1C,^[10] ILF2,^[9] Ataxia telangiectasia mutated,^[5][11] Ku80,^[12][13][14] CDC5L,^[15] P53,^[5][6][16] CIB1,^[17] C1D^[16] and CHUK.^[18]

See also

• Non-homologous end joining
• V(D)J recombination
• Ku
• Protein kinase

References

1. ^ Sipley JD, Menninger JC, Hartley KO, Ward DC, Jackson SP, Anderson CW (August 1995). "Gene for the catalytic subunit of the human DNA-activated protein kinase maps to the site of the XRCC7 gene on chromosome 8". Proc. Natl. Acad. Sci. U.S.A. 92 (16): 7515–9. doi:10.1073/pnas.92.16.7515. PMC 41370. PMID 7638222. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=41370. 
2. ^ "Entrez Gene: PRKDC protein kinase, DNA-activated, catalytic polypeptide". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5591. 
3. ^ Meek K, Dang V, Lees-Miller SP (2008). "DNA-PK: the means to justify the ends?". Adv. Immunol. 99: 33–58. doi:10.1016/S0065-2776(08)00602-0. PMID 19117531. 
4. ^ Ko, L; Cardona G R, Chin W W (May. 2000). "Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 97 (11): 6212–7. doi:10.1073/pnas.97.11.6212. ISSN 0027-8424. PMC 18584. PMID 10823961. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=18584. 
5. ^ ^{a b c d} Kim, S T; Lim D S, Canman C E, Kastan M B (Dec. 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. (UNITED STATES) 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. ISSN 0021-9258. PMID 10608806. 
6. ^ ^{a b} Goudelock, Dawn Marie; Jiang Kecheng, Pereira Elizabeth, Russell Beatriz, Sanchez Yolanda (Aug. 2003). "Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex". J. Biol. Chem. (United States) 278 (32): 29940–7. doi:10.1074/jbc.M301765200. ISSN 0021-9258. PMID 12756247. 
7. ^ Karmakar, Parimal; Piotrowski Jason, Brosh Robert M, Sommers Joshua A, Miller Susan P Lees, Cheng Wen-Hsing, Snowden Carey M, Ramsden Dale A, Bohr Vilhelm A (May. 2002). "Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation". J. Biol. Chem. (United States) 277 (21): 18291–302. doi:10.1074/jbc.M111523200. ISSN 0021-9258. PMID 11889123. 
8. ^ Shao, R G; Cao C X, Zhang H, Kohn K W, Wold M S, Pommier Y (Mar. 1999). "Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes". EMBO J. (ENGLAND) 18 (5): 1397–406. doi:10.1093/emboj/18.5.1397. ISSN 0261-4189. PMC 1171229. PMID 10064605. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1171229. 
9. ^ ^{a b} Ting, N S; Kao P N, Chan D W, Lintott L G, Lees-Miller S P (Jan. 1998). "DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45". J. Biol. Chem. (UNITED STATES) 273 (4): 2136–45. doi:10.1074/jbc.273.4.2136. ISSN 0021-9258. PMID 9442054. 
10. ^ Ma, Yunmei; Pannicke Ulrich, Schwarz Klaus, Lieber Michael R (Mar. 2002). "Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination". Cell (United States) 108 (6): 781–94. doi:10.1016/S0092-8674(02)00671-2. ISSN 0092-8674. PMID 11955432. 
11. ^ Suzuki, K; Kodama S, Watanabe M (Sep. 1999). "Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation". J. Biol. Chem. (UNITED STATES) 274 (36): 25571–5. doi:10.1074/jbc.274.36.25571. ISSN 0021-9258. PMID 10464290. 
12. ^ Jin, S; Kharbanda S, Mayer B, Kufe D, Weaver D T (Oct. 1997). "Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit". J. Biol. Chem. (UNITED STATES) 272 (40): 24763–6. doi:10.1074/jbc.272.40.24763. ISSN 0021-9258. PMID 9312071. 
13. ^ Matheos, Diamanto; Ruiz Marcia T, Price Gerald B, Zannis-Hadjopoulos Maria (Oct. 2002). "Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication". Biochim. Biophys. Acta (Netherlands) 1578 (1-3): 59–72. doi:10.1016/S0167-4781(02)00497-9. ISSN 0006-3002. PMID 12393188. 
14. ^ Gell, D; Jackson S P (Sep. 1999). "Mapping of protein-protein interactions within the DNA-dependent protein kinase complex". Nucleic Acids Res. (ENGLAND) 27 (17): 3494–502. doi:10.1093/nar/27.17.3494. PMC 148593. PMID 10446239. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=148593. 
15. ^ Ajuh, P; Kuster B, Panov K, Zomerdijk J C, Mann M, Lamond A I (Dec. 2000). "Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry". EMBO J. (ENGLAND) 19 (23): 6569–81. doi:10.1093/emboj/19.23.6569. ISSN 0261-4189. PMC 305846. PMID 11101529. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=305846. 
16. ^ ^{a b} Yavuzer, U; Smith G C, Bliss T, Werner D, Jackson S P (Jul. 1998). "DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D". Genes Dev. (UNITED STATES) 12 (14): 2188–99. doi:10.1101/gad.12.14.2188. ISSN 0890-9369. PMC 317006. PMID 9679063. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=317006. 
17. ^ Wu, X; Lieber M R (Oct. 1997). "Interaction between DNA-dependent protein kinase and a novel protein, KIP". Mutat. Res. (NETHERLANDS) 385 (1): 13–20. ISSN 0027-5107. PMID 9372844. 
18. ^ Liu, L; Kwak Y T, Bex F, García-Martínez L F, Li X H, Meek K, Lane W S, Gaynor R B (Jul. 1998). "DNA-dependent protein kinase phosphorylation of IkappaB alpha and IkappaB beta regulates NF-kappaB DNA binding properties". Mol. Cell. Biol. (UNITED STATES) 18 (7): 4221–34. ISSN 0270-7306. PMC 109006. PMID 9632806. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=109006. 

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