DNA-PKcs

Protein kinase, DNA-activated, catalytic polypeptide
Identifiers
Symbols PRKDC ; DNA-PKcs; DNAPK; DNPK1; HYRC; HYRC1; IMD26; XRCC7; p350
External IDs OMIM: 600899 MGI: 104779 HomoloGene: 5037 ChEMBL: 3142 GeneCards: PRKDC Gene
EC number 2.7.11.1
Orthologs
Species Human Mouse
Entrez 5591 19090
Ensembl ENSG00000253729 ENSMUSG00000022672
UniProt P78527 P97313
RefSeq (mRNA) NM_001081640 NM_011159
RefSeq (protein) NP_001075109 NP_035289
Location (UCSC) Chr 8:
47.77 – 47.96 Mb		 Chr 16:
15.64 – 15.84 Mb
PubMed search

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.

Aging

Non-homologous end joining (NHEJ) is the principal DNA repair process used by mammalian somatic cells to cope with double-strand breaks that continually occur in the genome. DNA-PKcs is one of the key components of the NHEJ machinery. DNA-PKcs deficient mice have a shorter lifespan and show an earlier onset of numerous aging related pathologies than corresponding wild-type littermates.[4][5] These findings suggest that failure to efficiently repair DNA double-strand breaks results in premature aging, consistent with the DNA damage theory of aging. (See also Bernstein et al.[6])

Interactions

DNA-PKcs has been shown to interact with:

See also

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.
  2. ↑ "Entrez Gene: PRKDC protein kinase, DNA-activated, catalytic polypeptide".
  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. ↑ Espejel S, Martín M, Klatt P, Martín-Caballero J, Flores JM, Blasco MA (2004). "Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice". EMBO Rep. 5 (5): 503–9. doi:10.1038/sj.embor.7400127. PMC 1299048. PMID 15105825.
  5. ↑ Reiling E, Dollé ME, Youssef SA, Lee M, Nagarajah B, Roodbergen M, de With P, de Bruin A, Hoeijmakers JH, Vijg J, van Steeg H, Hasty P (2014). "The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency". PLoS ONE 9 (4): e93568. doi:10.1371/journal.pone.0093568. PMC 3989187. PMID 24740260.
  6. ↑ Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 ISBN 978-1604565812
  7. 1 2 3 4 Kim ST, Lim DS, Canman CE, Kastan MB (December 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806.
  8. ↑ Suzuki K, Kodama S, Watanabe M (September 1999). "Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation". J. Biol. Chem. 274 (36): 25571–5. doi:10.1074/jbc.274.36.25571. PMID 10464290.
  9. 1 2 Yavuzer U, Smith GC, Bliss T, Werner D, Jackson SP (July 1998). "DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D". Genes Dev. 12 (14): 2188–99. doi:10.1101/gad.12.14.2188. PMC 317006. PMID 9679063.
  10. ↑ Ajuh P, Kuster B, Panov K, Zomerdijk JC, Mann M, Lamond AI (December 2000). "Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry". EMBO J. 19 (23): 6569–81. doi:10.1093/emboj/19.23.6569. PMC 305846. PMID 11101529.
  11. 1 2 Goudelock DM, Jiang K, Pereira E, Russell B, Sanchez Y (August 2003). "Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex". J. Biol. Chem. 278 (32): 29940–7. doi:10.1074/jbc.M301765200. PMID 12756247.
  12. ↑ Liu L, Kwak YT, Bex F, García-Martínez LF, Li XH, Meek K, Lane WS, Gaynor RB (July 1998). "DNA-dependent protein kinase phosphorylation of IkappaB alpha and IkappaB beta regulates NF-kappaB DNA binding properties". Mol. Cell. Biol. 18 (7): 4221–34. PMC 109006. PMID 9632806.
  13. ↑ Wu X, Lieber MR (October 1997). "Interaction between DNA-dependent protein kinase and a novel protein, KIP". Mutat. Res. 385 (1): 13–20. doi:10.1016/s0921-8777(97)00035-9. PMID 9372844.
  14. ↑ Ma Y, Pannicke U, Schwarz K, Lieber MR (March 2002). "Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination". Cell 108 (6): 781–94. doi:10.1016/s0092-8674(02)00671-2. PMID 11955432.
  15. 1 2 Ting NS, Kao PN, Chan DW, Lintott LG, Lees-Miller SP (January 1998). "DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45". J. Biol. Chem. 273 (4): 2136–45. doi:10.1074/jbc.273.4.2136. PMID 9442054.
  16. ↑ Jin S, Kharbanda S, Mayer B, Kufe D, Weaver DT (October 1997). "Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit". J. Biol. Chem. 272 (40): 24763–6. doi:10.1074/jbc.272.40.24763. PMID 9312071.
  17. ↑ Matheos D, Ruiz MT, Price GB, Zannis-Hadjopoulos M (October 2002). "Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication". Biochim. Biophys. Acta 1578 (1-3): 59–72. doi:10.1016/s0167-4781(02)00497-9. PMID 12393188.
  18. ↑ Gell D, Jackson SP (September 1999). "Mapping of protein-protein interactions within the DNA-dependent protein kinase complex". Nucleic Acids Res. 27 (17): 3494–502. doi:10.1093/nar/27.17.3494. PMC 148593. PMID 10446239.
  19. ↑ Ko L, Cardona GR, Chin WW (May 2000). "Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator". Proc. Natl. Acad. Sci. U.S.A. 97 (11): 6212–7. doi:10.1073/pnas.97.11.6212. PMC 18584. PMID 10823961.
  20. ↑ Shao RG, Cao CX, Zhang H, Kohn KW, Wold MS, Pommier Y (March 1999). "Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes". EMBO J. 18 (5): 1397–406. doi:10.1093/emboj/18.5.1397. PMC 1171229. PMID 10064605.
  21. ↑ Karmakar P, Piotrowski J, Brosh RM, Sommers JA, Miller SP, Cheng WH, Snowden CM, Ramsden DA, Bohr VA (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. 277 (21): 18291–302. doi:10.1074/jbc.M111523200. PMID 11889123.
This article is issued from Wikipedia - version of the Sunday, January 10, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.