Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

The EBNA- 3 gene family proteins disrupt the G2/M checkpoint

Oncogene volume 23, pages 1342–1353 (2004)Cite this article

Abstract

The Epstein–Barr nuclear antigens (EBNA), EBNA-3, -4 and -6, have previously been shown to act as transcriptional regulators, however, this study identifies another function for these proteins, disruption of the G2/M checkpoint. Lymphoblastoid cell lines (LCLs) treated with a G2/M initiating drug azelaic bishydroxamine (ABHA) did not show a G2/M checkpoint response, but rather they display an increase in cell death, a characteristic of sensitivity to the cytotoxic effects of the drug. Cell cycle analysis demonstrated that the individual expression of EBNA-3, -4 or -6 are capable of disrupting the G2/M checkpoint response induced by ABHA resulting in increased toxicity, whereas EBNA-2, and -5 were not. EBNA-3 gene family protein expression also disrupted the G2/M checkpoint initiated in response to the genotoxin etoposide and the S phase inhibitor hydroxyurea. The G2 arrest in response to these drugs were sensitive to caffeine, suggesting that ATM/ATR signalling in these checkpoint responses may be blocked by the EBNA-3 family proteins. The function of EBNA-3, -4 and -6 proteins appears to be more complex than anticipated and these data suggest a role for these proteins in disrupting the host cell cycle machinery.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Ben Bassat H, Goldblum N, Mitrani S, Goldblum T, Yoffey JM, Cohen MM, Bentwich Z, Ramot B, Klein E and Klein G . (1977). Int. J. Cancer, 19, 27–33.

    Article  Google Scholar 

  • Berezutskaya E, Yu B, Morozov A, Raychaudhuri P and Bagchi S . (1997). Cell Growth Differ., 8, 1277–1286.

  • Blasina A, Price BD, Turenne GA and McGowan CH . (1999). Curr. Biol., 9, 1135–1138.

  • Brondello JM, Boddy MN, Furnari B and Russell P . (1999). Mol. Cell. Biol., 19, 4262–4269.

    Article  CAS  Google Scholar 

  • Burgess AJ, Pavey S, Warrener R, Hunter LJ, Piva TJ, Musgrove EA, Saunders N, Parsons PG and Gabrielli BG . (2001). Mol. Pharmacol., 60, 828–837.

  • Cannell EJ, Farrell PJ and Sinclair AJ . (1996). Oncogene, 13, 1413–1421.

  • Chaturvedi P, Eng WK, Zhu Y, Mattern MR, Mishra R, Hurle MR, Zhang X, Annan RS, Lu Q, Faucette LF, Scott GF, Li X, Carr SA, Johnson RK, Winkler JD and Zhou BB . (1999). Oncogene, 18, 4047–4054.

    Article  CAS  Google Scholar 

  • Chehab NH, Malikzay A, Appel M and Halazonetis TD . (2000). Genes Dev., 14, 278–288.

  • Cludts I and Farrell PJ . (1998). J. Virol., 72, 1862–1869.

  • Connell MJ, Walworth NC and Carr AM . (2000). Trends Cell. Biol., 10, 296–303.

  • Darbon JM, Penary M, Escalas N, Casagrande F, Goubin-Gramatica F, Baudouin C and Ducommun B . (2000). J. Biol. Chem., 275, 15363–15369.

    Article  CAS  Google Scholar 

  • Elledge SJ . (1996). Science, 274, 1664–1672.

    Article  CAS  Google Scholar 

  • Enoch T and Nurse P . (1990). Cell, 60, 665–673.

    Article  CAS  Google Scholar 

  • Floettmann JE, Ward K, Rickinson AB and Rowe M . (1996). Virology, 223, 29–40.

    Article  CAS  Google Scholar 

  • Gabrielli BG, De Souza CP, Tonks ID, Clark JM, Hayward NK and Ellem KA . (1996). J. Cell Sci., 109, 1081–1093.

  • Goodwin EC and DiMaio D . (2000). Proc. Natl. Acad. Sci. USA, 97, 12513–12518.

  • Grundhoff AT, Kremmer E, Tureci O, Glieden A, Gindorf C, Atz J, Mueller-Lantzsch N, Schubach WH and Grasser FA . (1999). J. Biol. Chem., 274, 19136–19144.

    Article  CAS  Google Scholar 

  • Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ and Mak TW . (2000). Science, 287, 1824–1827.

    Article  CAS  Google Scholar 

  • Kaykas A and Sugden B . (2000). Oncogene, 19, 1400–1410.

    Article  CAS  Google Scholar 

  • Kienzle N, Young D, Silins SL and Sculley TB . (1996a). Virology, 224, 167–174.

    Article  CAS  Google Scholar 

  • Kienzle N, Young D, Zehntner S, Bushell G and Sculley TB . (1996b). Biotechniques, 20, 612–616.

  • Krauer KG, Kienzle N, Young DB and Sculley TB . (1996). Virology, 226, 346–353.

    Article  CAS  Google Scholar 

  • Kumagai A and Dunphy WG . (1991). Cell, 64, 903–914.

    Article  CAS  Google Scholar 

  • Lindsay HD, Griffiths DJ, Edwards RJ, Christensen PU, Murray JM, Osman F, Walworth N and Carr AM . (1998). Genes Dev., 12, 382–395.

  • Lock RB . (1992). Cancer Res., 52, 1817–1822.

  • Margolskee RF, Kavathas P and Berg P . (1988). Mol. Cell. Biol., 8, 2837–2847.

    Article  CAS  Google Scholar 

  • Marshall D and Sample C . (1995). J. Virol., 69, 3624–3630.

  • Matsuoka S, Huang M and Elledge SJ . (1998). Science, 282, 1893–1897.

    Article  CAS  Google Scholar 

  • Maunders MJ, Petti L and Rowe M . (1994). J. Gen. Virol., 75, 769–778.

  • Morgan DO . (1995). Nature, 374, 131–134.

    Article  CAS  Google Scholar 

  • Parker GA, Crook T, Bain M, Sara EA, Farrell PJ and Allday MJ . (1996). Oncogene, 13, 2541–2549.

  • Parker GA, Touitou R and Allday MJ . (2000). Oncogene, 19, 700–709.

    Article  CAS  Google Scholar 

  • Petti L, Sample C and Kieff E . (1990). Virology, 176, 563–574.

    Article  CAS  Google Scholar 

  • Pines J and Hunt T . (1987). EMBO J., 6, 2987–2995.

  • Qiu L, Burgess A, Fairlie DP, Leonard H, Parsons PG and Gabrielli BG . (2000). Mol. Biol. Cell., 11, 2069–2083.

  • Radkov SA, Touitou R, Brehm A, Rowe M, West M, Kouzarides T and Allday MJ . (1999). J. Virol., 73, 5688–5697.

  • Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA and Marks PA . (1998). Proc. Natl. Acad. Sci. USA, 95, 3003–3007.

  • Robertson ES, Lin J and Kieff E . (1996). J. Virol., 70, 3068–3074.

  • Sambrook J, Fritsch EF and Maniatis T . (1989). Molecular Cloning, A laboratory Manual, 3rd edn. Cold Spring Harbour Laboratory Press: Cold Spring Harbour, New York.

    Google Scholar 

  • Sculley TB, Buck M, Gabrielli B, Parsons PG and Krauer KG . (2002). Transplantation, 73, 271–279.

    Article  CAS  Google Scholar 

  • Sculley TB, Walker PJ, Moss DJ and Pope JH . (1984). J. Virol., 52, 88–93.

  • Shieh SY, Ahn J, Tamai K, Taya Y and Prives C . (2000). Genes Dev., 14, 289–300.

  • Silins SL and Sculley TB . (1994). Virology, 202, 16–24.

    Article  CAS  Google Scholar 

  • Sinclair AJ and Farrell PJ . (1992). Cell Growth Differ., 3, 557–563.

  • Sinclair AJ, Fenton M and Delikat S . (1998). Histol. Histopathol., 13, 461–467.

  • Sinclair AJ, Palmero I, Peters G and Farrell PJ . (1994). EMBO J., 13, 3321–3328.

  • Tomkinson B, Robertson E and Kieff E . (1993). J. Virol., 67, 2014–2025.

  • Villa LL . (1997). Adv. Cancer Res., 71, 321–341.

  • Wade M and Allday MJ . (2000). Mol. Cell. Biol., 20, 1344–1360.

  • Wang JH, Yan YW, Garrett TP, Liu JH, Rodgers DW, Garlick RL, Tarr GE, Husain Y, Reinherz EL and Harrison SC . (1990). Nature, 348, 411–418.

    Article  CAS  Google Scholar 

  • Westendorf JM, Rao PN and Gerace L . (1994). Proc. Natl. Acad. Sci. USA, 91, 714–718.

  • Zeng Y, Forbes KC, Wu Z, Moreno S, Piwnica-Worms H and Enoch T . (1998). Nature, 395, 507–510.

    Article  CAS  Google Scholar 

  • Zhao B, Marshall DR and Sample CE . (1996). J. Virol, 70, 4228–4236.

  • Zhou BB and Elledge SJ . (2000). Nature, 408, 433–439.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Thanks to Matthew P Glen (Centre for Drug Design and Development, University of Queensland) for synthesizing the ABHA used in the study. This work was supported by Research Grants provided by the National Health and Medial Research Council, Queensland Cancer Fund and the University of Queensland Cancer Fund. Brian Gabrielli is supported by a grant from the Australian Research Council. James Flanagan was supported by a scholarship provided by the University of Queensland Postgraduate Research Fund.

Author information

Author notes

  1. Andrew Burgess & Brian Gabrielli

    Present address: Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, 4102, Australia

Authors and Affiliations

  1. Queensland Institute of Medical Research and Joint Oncology Program, University of Queensland, Brisbane, Australia

    Kenia G Krauer, Marion Buck, James Flanagan & Tom B Sculley

  2. Department of Molecular and Cellular Pathology, University of Queensland, Brisbane, Australia

    Andrew Burgess & Brian Gabrielli

Authors
  1. Kenia G Krauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew Burgess
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marion Buck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James Flanagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tom B Sculley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Brian Gabrielli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenia G Krauer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krauer, K., Burgess, A., Buck, M. et al. The EBNA- 3 gene family proteins disrupt the G2/M checkpoint. Oncogene 23, 1342–1353 (2004). https://doi.org/10.1038/sj.onc.1207253

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207253

Keywords

This article is cited by

Search

Advanced search

Quick links