Apoptotic endonuclease EndoG induces alternative splicing of telomerase catalytic subunit hTERT and death of tumor cells

  • D. D. ZhdanovEmail author
  • D. A. Vasina
  • V. S. Orlova
  • V. Y. Gotovtseva
  • M. V. Bibikova
  • V. S. Pokrovsky
  • M. V. Pokrovskayaa
  • S. S. Aleksandrova
  • N. N. Sokolov


Telomerase activity is known to be regulated by alternative splicing of its catalytic subunit hTERT (human Telomerase Reverse Transcriptase) mRNA. Induction of non-active spliced hTERT leads to inhibition of telomerase activity. However, very little is known about the mechanism of hTERT mRNA alternative splicing. The aim of this study was to determine the role of apoptotic endonuclease EndoG in alternative splicing of hTERT and telomerase activity. Strong correlation was found between expression of EndoG and hTERT splice-variants in 12 colon cancer cell lines. Overexpression of EndoG in СаСо-2 cells downregulated the expression of active full-length hTERT variant and upregulated non-active spliced variant. Reduction of full-length hTERT caused downregulation of telomerase activity, dramatically shortening of telomeres length during cell divisions, converting cells to the replicative senescence state, activation of apoptosis and finally cell death. These data indicated the participation of EndoG in alternative splicing of mRNA of telomerase catalytic subunit, regulation of telomerase activity and cell fate.


EndoG telomerase hTERT alternative splicing CaCo-2 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Blackburn, E. H., Nature, 2000, vol. 408, pp. 53–56. doi 10.1038/35040500CrossRefGoogle Scholar
  2. 2.
    Harley, C.B., Futcher, A.B., and Greider, C.W., Nature, 1990, vol. 345, pp. 458–460. doi 10.1038/345458a0CrossRefGoogle Scholar
  3. 3.
    Ewald, J.A., Desotelle, J.A., Church, D.R., Yang, B., Huang, W., Laurila, T.A., and Jarrard, D.F., Prostate, 2013, vol. 73, pp. 337–345. doi 10.1002/pros.22571CrossRefGoogle Scholar
  4. 4.
    Lee, B.Y., Han, J.A., Im, J.S., Morrone, A., Johung, K., Goodwin, E.C., Kleijer, W.J., DiMaio, D., and Hwang, E.S., Aging Cell, 2006, vol. 5, pp. 187–195. doi 10.1111/j.1474-9726.2006.00199.xCrossRefGoogle Scholar
  5. 5.
    Kaszubowska, L., Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society, 2008, vol. 59, Suppl. 9, pp. 169–186.Google Scholar
  6. 6.
    Kim, N.W., Piatyszek, M.A., Prowse, K.R., Harley, C.B., West, M.D., Ho, P.L., Coviello, G.M., Wright, W.E., Weinrich, S.L., and Shay, J.W., Science, 1994, vol. 266, pp. 2011–2015.CrossRefGoogle Scholar
  7. 7.
    Meyerson, M., Counter, C.M., Eaton, E.N., Ellisen, L.W., Steiner, P., Caddle, S.D., Ziaugra, L., Beijersbergen, R.L., Davidoff, M.J., Liu, Q., Bacchetti, S., Haber, D.A., and Weinberg, R.A., Cell, 1997, vol. 90, pp. 785–795.CrossRefGoogle Scholar
  8. 8.
    Listerman, I., Sun, J., Gazzaniga, F.S., Lukas, J.L., and Blackburn. E.H., Cancer Research, 2013, vol. 73, pp. 2817–2828. doi 10.1158/0008-5472.CAN-12-3082CrossRefGoogle Scholar
  9. 9.
    Krams, M., Claviez, A., Heidorn, K., Krupp, G., Parwaresch, R., Harms, D., and Rudolph, P., American Journal of Pathology, 2001, vol. 159, pp. 1925–1932. doi 10.1016/S0002-9440(10)63039-8CrossRefGoogle Scholar
  10. 10.
    Daniel, M., Peek, G.W., and Tollefsbol, T.O., Gene, 2012, vol. 498, pp. 135–146. doi 10.1016/j.gene.2012.01.095CrossRefGoogle Scholar
  11. 11.
    Saebøe-Larssen, S., Fossberg, E., and Gaudernack, G., BMC Molecular Biology, 2006, vol. 7, pp. 26–32.CrossRefGoogle Scholar
  12. 12.
    Hrdlickov., tR., Nehyba, J., and Bose, H.R., Jr., {iMol. Cell Biol.,} 2012, vol. 32, no. 21, pp. 4283–4296. doi 10.1128/MCB.00550-12Google Scholar
  13. 13.
    Ulaner, G.A., Hu, J.F., Vu, T.H., Giudice, L.C., and Hoffman, A.R., Cancer Research, 1998, vol. 58, pp. 4168–4172.Google Scholar
  14. 14.
    Ulaner, G.A., Hu, J.F., Vu, T.H., Oruganti, H., Giudice, L.C., and Hoffman, A.R., International Journal of Cancer, 2000, vol. 85, pp. 330–335.CrossRefGoogle Scholar
  15. 15.
    Listerman, I., Sun, J., Gazzaniga, F.S., Lukas, J.L., and Blackburn, E.H., Cancer Research, 2013, vol. 73, pp. 2817–2828. doi 10.1158/0008-5472.CAN-12-3082CrossRefGoogle Scholar
  16. 16.
    Oulton, R. and Harrington, L., Molecular Biology of the Cell, 2004, vol. 15, pp. 3244–3256. doi 10.1091/mbc.E04-03-0178CrossRefGoogle Scholar
  17. 17.
    Lydeard, J.R., Jain, S., Yamaguchi, M., and Haber, J.E., Nature, 2007, vol. 448, pp. 820–823. doi 10.1038/nature06047CrossRefGoogle Scholar
  18. 18.
    Nagata, S., Nagase, H., Kawane, K., Mukae, N., and Fukuyama, H., Cell Death and Differentiation, 2003, vol. 10, pp. 108–116. doi 10.1038/sj.cdd.4401161CrossRefGoogle Scholar
  19. 19.
    Ruiz-Carrillo, A. and Renaud, J., EMBO Journal, 1987, vol. 6, pp. 401–407.Google Scholar
  20. 20.
    Diener, T., Neuhaus, M., Koziel, R., Micutkova, L., and Jansen-Dürr, P., Experimental Gerontology, 2010, vol. 45, pp. 638–644. doi 10.1016/j.exger.2010.03.002CrossRefGoogle Scholar
  21. 21.
    Basnakian, A.G., Apostolov, E.O., Yin, X., Abiri, S.O., Stewart, A.G., Singh, A.B., and Shah, S.V., Experimental Cell Research, 2006, vol. 312, pp. 4139–4149. doi 10.1016/j.yexcr.2006.09.012CrossRefGoogle Scholar
  22. 22.
    Bradford, M.M., Anal. Biochem., 1976, vol. 72, pp. 248–254.CrossRefGoogle Scholar
  23. 23.
    Laemmli, U.K., Nature, 1970, vol. 227, pp. 680–685.CrossRefGoogle Scholar
  24. 24.
    Hofnagel, O., Luechtenborg, B., Stolle, K., Lorkowski, S., Eschert, H., Plenz, G., and Robenek, H., Arteriosclerosis, Thrombosis, and Vascular Biology, 2004, vol. 24, pp. 1789–1795. doi 10.1161/01.ATV.0000140061.89096.2bCrossRefGoogle Scholar
  25. 25.
    Kovalenko, N.A., Zhdanov, D.D., Bibikova, M.V., and Gotovtseva, V.I., Biomed Khim., 2011, vol. 57, pp. 501–510.CrossRefGoogle Scholar
  26. 26.
    O’Callaghan, N.J. and Fenech, M., (2011) Biological Procedures Online, 2011, vol. 13, 3, doi 10.1186/1480-9222-13-3Google Scholar
  27. 27.
    Cawthon, R.M., Nucleic Acids Research, 2002, vol. 30, e47.CrossRefGoogle Scholar
  28. 28.
    Ruden, M. and Puri, N., Cancer Treatment Reviews, 2013, vol. 39, pp. 444–456.CrossRefGoogle Scholar
  29. 29.
    Read, M.A., Wood, A.A., Harrison, J.R., Gowan, S.M., Kelland, L.R., Dosanjh, H.S., and Neidle, S. J. Med. Chem., 1999, vol. 42, pp. 4538–4546.CrossRefGoogle Scholar
  30. 30.
    Zhou, Z., Du, Y., Zhang, L., and Dong, S., Biosens. Bioelectron., 2012, vol. 34, pp. 100–105. doi 10.1016/j.bios.2012.01.024CrossRefGoogle Scholar
  31. 31.
    Martadinata, H., Heddi, B., Lim, K.W., and Phan, A.T., Biochemistry, 2011, vol. 50, pp. 6455–6461. doi 10.1021/bi200569fCrossRefGoogle Scholar
  32. 32.
    Zhdanov, D.D., Fahmi, T., Wang, X., Apostolov, E.O., Sokolov, N.N., Javadov, S., and Basnakian, A.G., DNA Cell Biol., 2015, vol. 34, pp. 316–326. doi 10.1089/dna.2014.2772CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2016

Authors and Affiliations

  • D. D. Zhdanov
    • 1
    • 2
    Email author
  • D. A. Vasina
    • 2
  • V. S. Orlova
    • 2
  • V. Y. Gotovtseva
    • 3
  • M. V. Bibikova
    • 3
  • V. S. Pokrovsky
    • 1
  • M. V. Pokrovskayaa
    • 1
  • S. S. Aleksandrova
    • 1
  • N. N. Sokolov
    • 1
  1. 1.Institute of Biomedical ChemistryMoscowRussia
  2. 2.Ecological FacultyPeoples Friendship University of RussiaMoscowRussia
  3. 3.Viorin LLCMoscowRussia

Personalised recommendations