Biology:DNA-PKcs

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 consisting of 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.

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.

Disease

DNA-PKcs knockout mice have severe combined immunodeficiency due to their V(D)J recombination defect. Natural analogs of this knockout happen in mice, horses and dogs, also causing SCID.[6] Human SCID usually have other causes, but two cases related to mutations in this gene are also known.[7]

Cancer

DNA damage appears to be the primary underlying cause of cancer,[8] and deficiencies in DNA repair genes likely underlie many forms of cancer.[9][10] 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.[11][12] 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.[13] They were also found in 10% of breast and pancreatic cancers.[14]

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.[citation needed] 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:


DNA-PKcs Inhibitors

AZD7648,[50] M3814 (peposertib),[51] M9831 (VX-984)[52] and BAY-8400[53] have been described as potent and selective DNA-PKcs inhibitors.

See also

References

  1. ↑ "Gene for the catalytic subunit of the human DNA-activated protein kinase maps to the site of the XRCC7 gene on chromosome 8". Proceedings of the National Academy of Sciences of the United States of America 92 (16): 7515–7519. August 1995. doi:10.1073/pnas.92.16.7515. PMID 7638222. Bibcode: 1995PNAS...92.7515S. 
  2. ↑ "Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats". Nature 463 (7277): 118–121. January 2010. doi:10.1038/nature08648. PMID 20023628. 
  3. ↑ "DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product". Cell 82 (5): 849–856. September 1995. doi:10.1016/0092-8674(95)90482-4. PMID 7671312. 
  4. ↑ "Entrez Gene: PRKDC protein kinase, DNA-activated, catalytic polypeptide". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5591. 
  5. ↑ Chapter 2 DNA-PK. Advances in Immunology. 99. 2008. pp. 33–58. doi:10.1016/S0065-2776(08)00602-0. ISBN 9780123743251. 
  6. ↑ "SCID dogs: similar transplant potential but distinct intra-uterine growth defects and premature replicative senescence compared with SCID mice". Journal of Immunology 183 (4): 2529–2536. August 2009. doi:10.4049/jimmunol.0801406. PMID 19635917. 
  7. ↑ "DNA-PKcs chemical inhibition versus genetic mutation: Impact on the junctional repair steps of V(D)J recombination". Molecular Immunology 120: 93–100. April 2020. doi:10.1016/j.molimm.2020.01.018. PMID 32113132. 
  8. ↑ "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Molecular Cancer Research 6 (4): 517–524. April 2008. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632. 
  9. ↑ "The DNA damage response: ten years after". Molecular Cell 28 (5): 739–745. December 2007. doi:10.1016/j.molcel.2007.11.015. PMID 18082599. 
  10. ↑ "Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy". Clinical Cancer Research 20 (23): 5882–5887. December 2014. doi:10.1158/1078-0432.CCR-14-1165. PMID 25451105. 
  11. ↑ "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. August 2008. doi:10.1371/journal.pgen.1000155. PMID 18704159. 
  12. ↑ "DNA damage, homology-directed repair, and DNA methylation". PLOS Genetics 3 (7): e110. July 2007. doi:10.1371/journal.pgen.0030110. PMID 17616978. 
  13. ↑ "Targeted next-generation sequencing for molecular diagnosis of endometriosis-associated ovarian cancer". Journal of Molecular Medicine 94 (7): 835–847. July 2016. doi:10.1007/s00109-016-1395-2. PMID 26920370. 
  14. ↑ "Mutational analysis of thirty-two double-strand DNA break repair genes in breast and pancreatic cancers". Cancer Research 68 (4): 971–975. February 2008. doi:10.1158/0008-5472.CAN-07-6272. PMID 18281469. 
  15. ↑ "Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer". International Journal of Oncology 37 (6): 1547–1554. December 2010. doi:10.3892/ijo_00000808. PMID 21042724. 
  16. ↑ "DNA-PKcs expression predicts response to radiotherapy in prostate cancer". International Journal of Radiation Oncology, Biology, Physics 84 (5): 1179–1185. December 2012. doi:10.1016/j.ijrobp.2012.02.014. PMID 22494583. 
  17. ↑ "[Potentials of DNA-PKcs, Ku80, and ATM in enhancing radiosensitivity of cervical carcinoma cells]" (in zh). AI Zheng = Aizheng = Chinese Journal of Cancer 26 (7): 724–729. July 2007. PMID 17626748. 
  18. ↑ "Expressions of Ku70 and DNA-PKcs as prognostic indicators of local control in nasopharyngeal carcinoma". International Journal of Radiation Oncology, Biology, Physics 62 (5): 1451–1457. August 2005. doi:10.1016/j.ijrobp.2004.12.049. PMID 16029807. 
  19. ↑ "ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers". BBA Clinical 2: 10–17. December 2014. doi:10.1016/j.bbacli.2014.08.001. PMID 26674120. 
  20. ↑ "Loss of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in gastric cancers". Cancer Research and Treatment 37 (2): 98–102. April 2005. doi:10.4143/crt.2005.37.2.98. PMID 19956487. 
  21. ↑ "Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation". PLOS ONE 5 (7): e11397. July 2010. doi:10.1371/journal.pone.0011397. PMID 20617180. Bibcode: 2010PLoSO...511397Y. 
  22. ↑ "MicroRNA-101 is a potential prognostic indicator of laryngeal squamous cell carcinoma and modulates CDK8". Journal of Translational Medicine 13: 271. August 2015. doi:10.1186/s12967-015-0626-6. PMID 26286725. 
  23. ↑ "MicroRNA-101 suppresses migration and invasion via targeting vascular endothelial growth factor-C in hepatocellular carcinoma cells". Oncology Letters 11 (1): 433–438. January 2016. doi:10.3892/ol.2015.3832. PMID 26870229. 
  24. ↑ "Suppression of nonhomologous end joining repair by overexpression of HMGA2". Cancer Research 69 (14): 5699–5706. July 2009. doi:10.1158/0008-5472.CAN-08-4833. PMID 19549901. 
  25. ↑ "Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family". Clinical Cancer Research 14 (8): 2334–2340. April 2008. doi:10.1158/1078-0432.CCR-07-4667. PMID 18413822. 
  26. ↑ "Let-7a inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2 in nasopharyngeal carcinoma". Journal of Translational Medicine 13: 105. March 2015. doi:10.1186/s12967-015-0462-8. PMID 25884389. 
  27. ↑ "miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer". PLOS ONE 8 (1): e54398. 2013. doi:10.1371/journal.pone.0054398. PMID 23342147. Bibcode: 2013PLoSO...854398V. 
  28. ↑ "Altered expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) during gastric carcinogenesis and its clinical implications on gastric cancer". International Journal of Oncology 31 (4): 859–866. October 2007. doi:10.3892/ijo.31.4.859. PMID 17786318. 
  29. ↑ "Up-regulation of DNA-dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma". Cancer Science 94 (10): 894–900. October 2003. doi:10.1111/j.1349-7006.2003.tb01372.x. PMID 14556663. 
  30. ↑ "Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors". Science Translational Medicine 5 (189): 189ra78. June 2013. doi:10.1126/scitranslmed.3005814. PMID 23761041. 
  31. ↑ 31.0 31.1 31.2 "Role of DNA-dependent protein kinase catalytic subunit in cancer development and treatment". Translational Cancer Research 1 (1): 22–34. June 2012. doi:10.3978/j.issn.2218-676X.2012.04.01. PMID 22943041. 
  32. ↑ "Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice". EMBO Reports 5 (5): 503–509. May 2004. doi:10.1038/sj.embor.7400127. PMID 15105825. 
  33. ↑ "The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency". PLOS ONE 9 (4): e93568. 2014. doi:10.1371/journal.pone.0093568. PMID 24740260. Bibcode: 2014PLoSO...993568R. 
  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 "Substrate specificities and identification of putative substrates of ATM kinase family members". The Journal of Biological Chemistry 274 (53): 37538–37543. December 1999. doi:10.1074/jbc.274.53.37538. PMID 10608806. 
  36. ↑ "Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation". The Journal of Biological Chemistry 274 (36): 25571–25575. September 1999. doi:10.1074/jbc.274.36.25571. PMID 10464290. 
  37. ↑ 37.0 37.1 "DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D". Genes & Development 12 (14): 2188–2199. July 1998. doi:10.1101/gad.12.14.2188. PMID 9679063. 
  38. ↑ "Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry". The EMBO Journal 19 (23): 6569–6581. December 2000. doi:10.1093/emboj/19.23.6569. PMID 11101529. 
  39. ↑ 39.0 39.1 "Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex". The Journal of Biological Chemistry 278 (32): 29940–29947. August 2003. doi:10.1074/jbc.M301765200. PMID 12756247. 
  40. ↑ "DNA-dependent protein kinase phosphorylation of IkappaB alpha and IkappaB beta regulates NF-kappaB DNA binding properties". Molecular and Cellular Biology 18 (7): 4221–4234. July 1998. doi:10.1128/MCB.18.7.4221. PMID 9632806. 
  41. ↑ "Interaction between DNA-dependent protein kinase and a novel protein, KIP". Mutation Research 385 (1): 13–20. October 1997. doi:10.1016/s0921-8777(97)00035-9. PMID 9372844. 
  42. ↑ "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): 781–794. March 2002. doi:10.1016/s0092-8674(02)00671-2. PMID 11955432. 
  43. ↑ 43.0 43.1 "DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45". The Journal of Biological Chemistry 273 (4): 2136–2145. January 1998. doi:10.1074/jbc.273.4.2136. PMID 9442054. 
  44. ↑ "Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit". The Journal of Biological Chemistry 272 (40): 24763–24766. October 1997. doi:10.1074/jbc.272.40.24763. PMID 9312071. 
  45. ↑ "Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1578 (1–3): 59–72. October 2002. doi:10.1016/s0167-4781(02)00497-9. PMID 12393188. 
  46. ↑ "Mapping of protein-protein interactions within the DNA-dependent protein kinase complex". Nucleic Acids Research 27 (17): 3494–3502. September 1999. doi:10.1093/nar/27.17.3494. PMID 10446239. 
  47. ↑ "Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator". Proceedings of the National Academy of Sciences of the United States of America 97 (11): 6212–6217. May 2000. doi:10.1073/pnas.97.11.6212. PMID 10823961. Bibcode: 2000PNAS...97.6212K. 
  48. ↑ "Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes". The EMBO Journal 18 (5): 1397–1406. March 1999. doi:10.1093/emboj/18.5.1397. PMID 10064605. 
  49. ↑ "Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation". The Journal of Biological Chemistry 277 (21): 18291–18302. May 2002. doi:10.1074/jbc.M111523200. PMID 11889123. 
  50. ↑ Goldberg, Frederick W.; Finlay, M. Raymond V.; Ting, Attilla K. T.; Beattie, David; Lamont, Gillian M.; Fallan, Charlene; Wrigley, Gail L.; Schimpl, Marianne et al. (2020). "The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor". Journal of Medicinal Chemistry 63 (7): 3461–3471. doi:10.1021/acs.jmedchem.9b01684. PMID 31851518. 
  51. ↑ "Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models". Molecular Cancer Therapeutics. https://aacrjournals.org/mct/article/19/5/1091/92835/Pharmacologic-Inhibitor-of-DNA-PK-M3814. 
  52. ↑ Khan, Atif J.; Misenko, Sarah M.; Thandoni, Aditya; Schiff, Devora; Jhawar, Sachin R.; Bunting, Samuel F.; Haffty, Bruce G. (2018). "VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells". Oncotarget 9 (40): 25833–25841. doi:10.18632/oncotarget.25383. PMID 29899825. PMC 5995231. https://www.oncotarget.com/article/25383/text/. 
  53. ↑ Berger, Markus; Wortmann, Lars; Buchgraber, Philipp; Lücking, Ulrich; Zitzmann-Kolbe, Sabine; Wengner, Antje M.; Bader, Benjamin; Bömer, Ulf et al. (2021). "BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies". Journal of Medicinal Chemistry 64 (17): 12723–12737. doi:10.1021/acs.jmedchem.1c00762. PMID 34428039. 



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