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.

  • Short Communication
  • Published:

Viral oncoproteins target the DNA methyltransferases

Abstract

Small DNA tumour viruses have evolved a number of mechanisms to drive nondividing cells into S phase. Virally encoded oncoproteins such as adenovirus E1A and human papillomavirus (HPV) E7 can bind an array of cellular proteins to override proliferation arrest. The DNA methyltransferase Dnmt1 is the major mammalian enzyme responsible for maintaining CpG methylation patterns in the cell following replication. One of the hallmarks of tumour cells is disrupted DNA methylation patterns, highlighting the importance of the proper regulation of DNA methyltransferases in normal cell proliferation. Here, we show that adenovirus 5 E1A and HPV-16 E7 associate in vitro and in vivo with the DNA methyltransferase Dnmt1. Consistent with this interaction, we find that E1A and E7 can purify DNA methyltransferase activity from nuclear extracts. These associations are direct and mediated by the extreme N-terminus of E1A and the CR3 zinc-finger domain of E7. Furthermore, we find that a point mutant at leucine 20 of E1A, a residue known to be critical for its transformation functions, is unable to bind Dnmt1 and DNA methyltransferase activity. Finally, both E1A and E7 can stimulate the methyltransferase activity of Dnmt1 in vitro. Our results provide the first indication that viral oncoproteins bind and regulate Dnmt1 enzymatic activity. These observations open up the possibility that this association may be used to control cellular proliferation pathways and suggest a new mechanism by which small DNA tumour viruses can steer cells through the cell cycle.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Ait-Si-Ali S, Ramirez S, Barre FX, Dkhissi F, Magnaghi-Jaulin L, Girault JA et al. (1998). Histone acetyltransferase activity of CBP is controlled by cycle-dependent kinases and oncoprotein E1A. Nature 396: 184–186.

    Article  CAS  Google Scholar 

  • Boyd JM, Loewenstein PM, Tang QQ, Yu L, Green M . (2002). Adenovirus E1A N-terminal amino acid sequence requirements for repression of transcription in vitro and in vivo correlate with those required for E1A interference with TBP-TATA complex formation. J Virol 76: 1461–1474.

    Article  CAS  Google Scholar 

  • Brenner C, Deplus R, Didelot C, Loriot A, Vire E, De Smet C et al. (2005). Myc represses transcription through recruitment of DNA methyltransferase corepressor. Embo J 24: 336–346.

    Article  CAS  Google Scholar 

  • Chakravarti D, Ogryzko V, Kao HY, Nash A, Chen H, Nakatani Y et al. (1999). A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity. Cell 96: 393–403.

    Article  CAS  Google Scholar 

  • de Bustros A, Nelkin BD, Silverman A, Ehrlich G, Poiesz B, Baylin SB . (1988). The short arm of chromosome 11 is a ‘hot spot’ for hypermethylation in human neoplasia. Proc Natl Acad Sci USA 85: 5693–5697.

    Article  CAS  Google Scholar 

  • Deplus R, Brenner C, Burgers WA, Putmans P, Kouzarides T, de Launoit Y et al. (2002). Dnmt3L is a transcriptional repressor that recruits histone deacetylase. Nucleic Acids Res 30: 3831–3838.

    Article  CAS  Google Scholar 

  • Frisch SM, Mymryk JS . (2002). Adenovirus-5 E1A: paradox and paradigm. Nat Rev Mol Cell Biol 3: 441–452.

    Article  CAS  Google Scholar 

  • Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T . (2000). DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 24: 88–91.

    Article  CAS  Google Scholar 

  • Fuks F . (2005). DNA methylation and histone modifications: teaming up to silence genes. Curr Opin Genet Dev 15: 490–495.

    Article  CAS  Google Scholar 

  • Gowher H, Liebert K, Hermann A, Xu G, Jeltsch A . (2005). Mechanism of stimulation of catalytic activity of Dnmt3A and Dnmt3B DNA-(cytosine-C5)-methyltransferases by Dnmt3L. J Biol Chem 280: 13341–13348.

    Article  CAS  Google Scholar 

  • Jones PA, Baylin SB . (2002). The fundamental role of epigenetic events in cancer. Nat Rev Genet 3: 415–428.

    Article  CAS  Google Scholar 

  • Laird PW, Jackson-Grusby L, Fazeli A, Dickinson SL, Jung WE, Li E et al. (1995). Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81: 197–205.

    Article  CAS  Google Scholar 

  • McCance DJ . (2005). Transcriptional regulation by human papillomaviruses. Curr Opin Genet Dev 15: 515–519.

    Article  CAS  Google Scholar 

  • Mikovits JA, Young HA, Vertino P, Issa JP, Pitha PM, Turcoski-Corrales S et al. (1998). Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-gamma) promoter and subsequent downregulation of IFN-gamma production. Mol Cell Biol 18: 5166–5177.

    Article  CAS  Google Scholar 

  • Ordway JM, Fenster SD, Ruan H, Curran T . (2005). A transcriptome map of cellular transformation by the fos oncogene. Mol Cancer 4: 19.

    Article  Google Scholar 

  • Pradhan S, Bacolla A, Wells RD, Roberts RJ . (1999). Recombinant human DNA (cytosine-5) methyltransferase I. Expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem 274: 33002–33010.

    Article  CAS  Google Scholar 

  • Pradhan S, Kim GD . (2002). The retinoblastoma gene product interacts with maintenance human DNA (cytosine-5) methyltransferase and modulates its activity. EMBO J 21: 779–788.

    Article  CAS  Google Scholar 

  • Robertson KD . (2001). DNA methylation, methyltransferases, and cancer. Oncogene 20: 3139–3155.

    Article  CAS  Google Scholar 

  • Sang N, Giordano A . (1997). Extreme N terminus of E1A oncoprotein specifically associates with a new set of cellular proteins. J Cell Physiol 170: 182–191.

    Article  CAS  Google Scholar 

  • Slack A, Cervoni N, Pinard M, Szyf M . (1999). DNA methyltransferase is a downstream effector of cellular transformation triggered by simian virus 40 large T antigen. J Biol Chem 274: 10105–10112.

    Article  CAS  Google Scholar 

  • Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C et al. (2006). The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439: 871–874.

    Article  CAS  Google Scholar 

  • Wang HG, Yaciuk P, Ricciardi RP, Green M, Yokoyama K, Moran E . (1993). The E1A products of oncogenic adenovirus serotype 12 include amino-terminally modified forms able to bind the retinoblastoma protein but not p300. J Virol 67: 4804–4813.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Whyte P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA et al. (1988). Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature 334: 124–129.

    Article  CAS  Google Scholar 

  • Wu J, Issa JP, Herman J, Bassett Jr DE, Nelkin BD, Baylin SB . (1993). Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. Proc Natl Acad Sci USA 90: 8891–8895.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B Moran for the kind gift of E1A constructs. WAB was supported by a scholarship from the National Research Foundation of South Africa. LB was supported by the FNRS and the ‘Fondation pour la Recherche Médicale’. SP was supported by NEB. FF is a ‘Chercheur Qualifié du FNRS’. This work was funded by a programme grant from the Cancer Research Campaign to TK and by grants from the ‘Fédération Belge contre le Cancer’, the FNRS, ‘FB Assurances’, and ‘ARC de la Communauté Française de Belgique’ to YdL and FF.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F Fuks.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burgers, W., Blanchon, L., Pradhan, S. et al. Viral oncoproteins target the DNA methyltransferases. Oncogene 26, 1650–1655 (2007). https://doi.org/10.1038/sj.onc.1209950

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209950

Keywords

This article is cited by

Search

Quick links