DNA-PKcs

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DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as PRKDC or XRCC7.[1] DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. The DNA-Pkcs protein is a serine/threonine protein kinase comprising a single polypeptide chain of 4,128 amino acids.[2][3]

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.[4] 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.[5] DNA-PK also cooperates with ATR and ATM to phosphorylate proteins involved in the DNA damage checkpoint.

Cancer

DNA damage appears to be the primary underlying cause of cancer,[6][7] and deficiencies in DNA repair genes likely underlie many forms of cancer.[8][9] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair.[10][11] Such mutations and epigenetic alterations may give rise to cancer.

PRKDC (DNA-PKcs) mutations were found in 3 out of 10 of endometriosis-associated ovarian cancers, as well as in the field defects from which they arose.[12] They were also found in 10% of breast and pancreatic cancers.[13]

Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are ordinarily even more frequent than mutational defects in DNA repair genes in cancers.[14] DNA-PKcs expression was reduced by 23% to 57% in six cancers as indicated in the table.

Frequency of reduced expression of DNA-PKcs in sporadic cancers
Cancer Frequency of reduction in cancer Ref.
Breast cancer 57% [15]
Prostate cancer 51% [16]
Cervical carcinoma 32% [17]
Nasopharyngeal carcinoma 30% [18]
Epithelial ovarian cancer 29% [19]
Gastric cancer 23% [20]

It is not clear what causes reduced expression of DNA-PKcs in cancers. MicroRNA-101 targets DNA-PKcs via binding to the 3'- UTR of DNA-PKcs mRNA and efficiently reduces protein levels of DNA-PKcs.[21] But miR-101 is more often decreased in cancers, rather than increased.[22][23]

HMGA2 protein could also have an effect on DNA-PKcs. HMGA2 delays the release of DNA-PKcs from sites of double-strand breaks, interfering with DNA repair by non-homologous end joining and causing chromosomal aberrations.[24] The let-7a microRNA normally represses the HMGA2 gene.[25][26] In normal adult tissues, almost no HMGA2 protein is present. In many cancers, let-7 microRNA is repressed. As an example, in breast cancers the promoter region controlling let-7a-3/let-7b microRNA is frequently repressed by hypermethylation.[27] Epigenetic reduction or absence of let-7a microRNA allows high expression of the HMGA2 protein and this would lead to defective expression of DNA-PKcs.

DNA-PKcs can be up-regulated by stressful conditions such as in Helicobacter pylori-associated gastritis.[28] After ionizing radiation DNA-PKcs was increased in the surviving cells of oral squamous cell carcinoma tissues.[29]

The ATM protein is important in homologous recombinational repair (HRR) of DNA double strand breaks. When cancer cells are deficient in ATM the cells are "addicted" to DNA-PKcs, important in the alternative DNA repair pathway for double-strand breaks, non-homologous end joining (NHEJ).[30] That is, in ATM-mutant cells, an inhibitor of DNA-PKcs causes high levels of apoptotic cell death. In ATM mutant cells, additional loss of DNA-PKcs leaves the cells without either major pathway (HRR and NHEJ) for repair of DNA double-strand breaks.

Elevated DNA-PKcs expression is found in a large fraction (40% to 90%) of some cancers (the remaining fraction of cancers often has reduced or absent expression of DNA-PKcs). The elevation of DNA-PKcs is thought to reflect the induction of a compensatory DNA repair capability, due to the genome instability in these cancers.[31] (As indicated in the article Genome instability, such genome instability may be due to deficiencies in other DNA repair genes present in the cancers.) Elevated DNA-PKcs is thought to be "beneficial to the tumor cells",[31] though it would be at the expense of the patient. As indicated in a table listing 12 types of cancer reported in 20 publications,[31] the fraction of cancers with over-expression of DNA-PKcs is often associated with an advanced stage of the cancer and shorter survival time for the patient. However, the table also indicates that for some cancers, the fraction of cancers with reduced or absent DNA-PKcs is also associated with advanced stage and poor patient survival.

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.[32][33] 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.[34])

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. ↑ Sibanda BL, Chirgadze DY, Blundell TL (2010). "Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats". Nature. 463 (7277): 118–21. doi:10.1038/nature08648. PMC 2811870. PMID 20023628.
  3. ↑ Hartley KO, Gell D, Smith GC, Zhang H, Divecha N, Connelly MA, Admon A, Lees-Miller SP, Anderson CW, Jackson SP (1995). "DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product". Cell. 82 (5): 849–56. doi:10.1016/0092-8674(95)90482-4. PMID 7671312.
  4. ↑ "Entrez Gene: PRKDC protein kinase, DNA-activated, catalytic polypeptide".
  5. ↑ Meek K, Dang V, Lees-Miller SP (2008). DNA-PK: the means to justify the ends?. Adv. Immunol. Advances in Immunology. 99. pp. 33–58. doi:10.1016/S0065-2776(08)00602-0. ISBN 9780123743251. PMID 19117531.
  6. ↑ Kastan MB (2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol. Cancer Res. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632.
  7. ↑ Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer
  8. ↑ Harper JW, Elledge SJ (2007). "The DNA damage response: ten years after". Mol. Cell. 28 (5): 739–45. doi:10.1016/j.molcel.2007.11.015. PMID 18082599.
  9. ↑ Dietlein F, Reinhardt HC (2014). "Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy". Clin. Cancer Res. 20 (23): 5882–7. doi:10.1158/1078-0432.CCR-14-1165. PMID 25451105.
  10. ↑ O'Hagan HM, Mohammad HP, Baylin SB (2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLoS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159.
  11. ↑ Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV (Jul 2007). "DNA damage, homology-directed repair, and DNA methylation". PLoS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978.
  12. ↑ Er TK, Su YF, Wu CC, Chen CC, Wang J, Hsieh TH, Herreros-Villanueva M, Chen WT, Chen YT, Liu TC, Chen HS, Tsai EM (2016). "Targeted next-generation sequencing for molecular diagnosis of endometriosis-associated ovarian cancer". J. Mol. Med. 94 (7): 835–47. doi:10.1007/s00109-016-1395-2. PMID 26920370.
  13. ↑ Wang X, Szabo C, Qian C, Amadio PG, Thibodeau SN, Cerhan JR, Petersen GM, Liu W, Couch FJ (2008). "Mutational analysis of thirty-two double-strand DNA break repair genes in breast and pancreatic cancers". Cancer Res. 68 (4): 971–5. doi:10.1158/0008-5472.CAN-07-6272. PMID 18281469.
  14. ↑ Carol Bernstein and Harris Bernstein (2015). Epigenetic Reduction of DNA Repair in Progression to Cancer, Advances in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-2209-8, InTech, Available from: http://www.intechopen.com/books/advances-in-dna-repair/epigenetic-reduction-of-dna-repair-in-progression-to-cancer
  15. ↑ Söderlund Leifler K, Queseth S, Fornander T, Askmalm MS (2010). "Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer". Int. J. Oncol. 37 (6): 1547–54. doi:10.3892/ijo_00000808. PMID 21042724.
  16. ↑ Bouchaert P, Guerif S, Debiais C, Irani J, Fromont G (2012). "DNA-PKcs expression predicts response to radiotherapy in prostate cancer". Int. J. Radiat. Oncol. Biol. Phys. 84 (5): 1179–85. doi:10.1016/j.ijrobp.2012.02.014. PMID 22494583.
  17. ↑ Zhuang L, Yu SY, Huang XY, Cao Y, Xiong HH (2007). "[Potentials of DNA-PKcs, Ku80, and ATM in enhancing radiosensitivity of cervical carcinoma cells]". AI Zheng (in Chinese). 26 (7): 724–9. PMID 17626748.
  18. ↑ Lee SW, Cho KJ, Park JH, Kim SY, Nam SY, Lee BJ, Kim SB, Choi SH, Kim JH, Ahn SD, Shin SS, Choi EK, Yu E (2005). "Expressions of Ku70 and DNA-PKcs as prognostic indicators of local control in nasopharyngeal carcinoma". Int. J. Radiat. Oncol. Biol. Phys. 62 (5): 1451–7. doi:10.1016/j.ijrobp.2004.12.049. PMID 16029807.
  19. ↑ Abdel-Fatah TM, Arora A, Moseley P, Coveney C, Perry C, Johnson K, Kent C, Ball G, Chan S, Madhusudan S (2014). "ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers". BBA Clinical. 2: 10–7. doi:10.1016/j.bbacli.2014.08.001. PMC 4633921. PMID 26674120.
  20. ↑ Lee HS, Yang HK, Kim WH, Choe G (2005). "Loss of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in gastric cancers". Cancer Res Treat. 37 (2): 98–102. doi:10.4143/crt.2005.37.2.98. PMC 2785401. PMID 19956487.
  21. ↑ Yan D, Ng WL, Zhang X, Wang P, Zhang Z, Mo YY, Mao H, Hao C, Olson JJ, Curran WJ, Wang Y (2010). "Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation". PLoS ONE. 5 (7): e11397. doi:10.1371/journal.pone.0011397. PMC 2895662. PMID 20617180.
  22. ↑ Li M, Tian L, Ren H, Chen X, Wang Y, Ge J, Wu S, Sun Y, Liu M, Xiao H (2015). "MicroRNA-101 is a potential prognostic indicator of laryngeal squamous cell carcinoma and modulates CDK8". J Transl Med. 13: 271. doi:10.1186/s12967-015-0626-6. PMC 4545549. PMID 26286725.
  23. ↑ Liu Z, Wang J, Mao Y, Zou B, Fan X (2016). "MicroRNA-101 suppresses migration and invasion via targeting vascular endothelial growth factor-C in hepatocellular carcinoma cells". Oncol Lett. 11 (1): 433–438. doi:10.3892/ol.2015.3832. PMC 4727073. PMID 26870229.
  24. ↑ Li AY, Boo LM, Wang SY, Lin HH, Wang CC, Yen Y, Chen BP, Chen DJ, Ann DK (2009). "Suppression of nonhomologous end joining repair by overexpression of HMGA2". Cancer Res. 69 (14): 5699–706. doi:10.1158/0008-5472.CAN-08-4833. PMC 2737594. PMID 19549901.
  25. ↑ Motoyama K, Inoue H, Nakamura Y, Uetake H, Sugihara K, Mori M (2008). "Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family". Clin. Cancer Res. 14 (8): 2334–40. doi:10.1158/1078-0432.CCR-07-4667. PMID 18413822.
  26. ↑ Wu A, Wu K, Li J, Mo Y, Lin Y, Wang Y, Shen X, Li S, Li L, Yang Z (2015). "Let-7a inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2 in nasopharyngeal carcinoma". J Transl Med. 13: 105. doi:10.1186/s12967-015-0462-8. PMC 4391148. PMID 25884389.
  27. ↑ Vrba L, Muñoz-Rodríguez JL, Stampfer MR, Futscher BW (2013). "miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer". PLoS ONE. 8 (1): e54398. doi:10.1371/journal.pone.0054398. PMC 3547033. PMID 23342147.
  28. ↑ Lee HS, Choe G, Park KU, Park do J, Yang HK, Lee BL, Kim WH (2007). "Altered expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) during gastric carcinogenesis and its clinical implications on gastric cancer". Int. J. Oncol. 31 (4): 859–66. doi:10.3892/ijo.31.4.859. PMID 17786318.
  29. ↑ Shintani S, Mihara M, Li C, Nakahara Y, Hino S, Nakashiro K, Hamakawa H (2003). "Up-regulation of DNA-dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma". Cancer Sci. 94 (10): 894–900. doi:10.1111/j.1349-7006.2003.tb01372.x. PMID 14556663.
  30. ↑ Riabinska A, Daheim M, Herter-Sprie GS, Winkler J, Fritz C, Hallek M, Thomas RK, Kreuzer KA, Frenzel LP, Monfared P, Martins-Boucas J, Chen S, Reinhardt HC (2013). "Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors". Sci Transl Med. 5 (189): 189ra78. doi:10.1126/scitranslmed.3005814. PMID 23761041.
  31. ↑ 31.0 31.1 31.2 Hsu FM, Zhang S, Chen BP (2012). "Role of DNA-dependent protein kinase catalytic subunit in cancer development and treatment". Transl Cancer Res. 1 (1): 22–34. doi:10.3978/j.issn.2218-676X.2012.04.01. PMC 3431019. PMID 22943041.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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
  35. ↑ 35.0 35.1 35.2 35.3 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.
  36. ↑ 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.
  37. ↑ 37.0 37.1 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.
  38. ↑ 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.
  39. ↑ 39.0 39.1 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.
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ 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.
  43. ↑ 43.0 43.1 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.
  44. ↑ 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.
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ 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.
  48. ↑ 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.
  49. ↑ 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.
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