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
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
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.
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.
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.
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.
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.
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.
Frisch SM, Mymryk JS . (2002). Adenovirus-5 E1A: paradox and paradigm. Nat Rev Mol Cell Biol 3: 441–452.
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.
Fuks F . (2005). DNA methylation and histone modifications: teaming up to silence genes. Curr Opin Genet Dev 15: 490–495.
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.
Jones PA, Baylin SB . (2002). The fundamental role of epigenetic events in cancer. Nat Rev Genet 3: 415–428.
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.
McCance DJ . (2005). Transcriptional regulation by human papillomaviruses. Curr Opin Genet Dev 15: 515–519.
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.
Ordway JM, Fenster SD, Ruan H, Curran T . (2005). A transcriptome map of cellular transformation by the fos oncogene. Mol Cancer 4: 19.
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.
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.
Robertson KD . (2001). DNA methylation, methyltransferases, and cancer. Oncogene 20: 3139–3155.
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.
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.
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.
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.
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.
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.
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
Corresponding author
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209950
Keywords
This article is cited by
-
Human papillomavirus E7 protein induces homologous recombination defects and PARPi sensitivity
Journal of Cancer Research and Clinical Oncology (2024)
-
HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management
Nature Reviews Clinical Oncology (2022)
-
Prevalence of Human Papillomavirus and Mouse Mammary Tumor Virus Like DNAs in Tumors from Moroccan Breast Cancer Patients
Indian Journal of Gynecologic Oncology (2022)
-
Type 2 human papillomavirus E7 attenuates E-cadherin expression in human keratinocytes
Journal of Microbiology (2021)
-
Differential Wnt-β- catenin pathway activation in HPV positive and negative oral epithelium is transmitted during head and neck tumorigenesis: clinical implications
Medical Microbiology and Immunology (2021)