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 Article
  • Published:

Tip60 degradation by adenovirus relieves transcriptional repression of viral transcriptional activator EIA

Oncogene volume 32, pages 5017–5025 (2013)Cite this article

Subjects

Abstract

Adenoviruses are linear double-stranded DNA viruses that infect human and rodent cell lines, occasionally transform them and cause tumors in animal models. The host cell challenges the virus in multifaceted ways to restrain viral gene expression and DNA replication, and sometimes even eliminates the infected cells by programmed cell death. To combat these challenges, adenoviruses abrogate the cellular DNA damage response pathway. Tip60 is a lysine acetyltransferase that acetylates histones and other proteins to regulate gene expression, DNA damage response, apoptosis and cell cycle regulation. Tip60 is a bona fide tumor suppressor as mice that are haploid for Tip60 are predisposed to tumors. We have discovered that Tip60 is degraded by adenovirus oncoproteins EIB55K and E4orf6 by a proteasome-mediated pathway. Tip60 binds to the immediate early adenovirus promoter and suppresses adenovirus EIA gene expression, which is a master regulator of adenovirus transcription, at least partly through retention of the virally encoded repressor pVII on this promoter. Thus, degradation of Tip60 by the adenoviral early proteins is important for efficient viral early gene transcription and for changes in expression of cellular genes.

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

  1. Moran E . Interaction of adenoviral proteins with pRB and p53. FASEB J 1993; 7: 880–885.

    Article  CAS  PubMed  Google Scholar 

  2. Whyte P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA et al. Association between an oncogenes and an anti-oncogene: the adenovirus EIA protein binds to retinoblastoma gene product. Nature 1988; 334: 124–129.

    Article  CAS  PubMed  Google Scholar 

  3. DeCapri JA, Ludlow JW, Figge J, Shew JY, Huang CM, Lee WH et al. (1988) SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 1988; 54: 275–283.

    Article  Google Scholar 

  4. Querido E, Blanchette P, Yan Q, Kamura T, Morrison M, Boivin D et al. Degradation of p53 by adenovirus E4orf6 and EIB55k proteins occurs via a novel mechanism involving a cullin containing complex. Genes Dev 2001; 15: 3104–3117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Stracker TH, Carson CT, Weitzman MD . Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature 2002; 418: 348–352.

    Article  CAS  PubMed  Google Scholar 

  6. Baker A, Rohleder KJ, Hanakahi LA, Ketner G . Adenovirus E4 34K and E1b55K oncoproteins target host DNA ligase IV for proteasomal degradation. J Virol 2007; 81: 7034–7040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dallaire F, Blanchette P, Groitl P, Dobner T, Branton PE . Identification of integrin alpha3 as a new substrate of the adenovirus E4orf6/E1B55- kilodalton E3 ubiquitin ligase complex. J Virol 2009; 83: 5329–5338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Blackford AN, Patel RN, Forrester NA, Theil K, Groitl P, Stewart GS et al. Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation. Proc Natl Acad Sci USA 2010; 107: 12251–12256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Seligson DB, McBrian MA, Mah V, Yu H, Tze S, Wang Q et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol 2009; 174: 1619–1628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ferrari R, Berk AJ, Kurdistani SK . Viral manipulation of the host epigenome for oncogenic transformation. Nat Rev 2009; 10: 290–294.

    Article  CAS  Google Scholar 

  11. Niller HH, Wolf H, Minarovits J . Viral hit and run oncogenesis: genetic and epigenetic scenarios. Cancer Lett 2011; 305: 200–217.

    Article  CAS  PubMed  Google Scholar 

  12. Jha S, Pol SV, Banerjee NM, Dutta AB, Chow LT, Dutta A . Destabilization of Tip60 by human Papillomavirus E6 results in attenuation of Tip60 dependent transcriptional regulation and apoptotic pathway. Mol Cell 2010; 38: 700–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Reitsma JM, Savaryn JP, Faust K, Sato H, Halligan BD, Scott ST . Antiviral inhibition targeting the HCMV kinase pUL97 requires pUL27 dependent degradation of Tip60 acetyltransferase and cell cycle arrest. Cell Host Microbe 2011; 9: 103–114.

    Article  CAS  PubMed  Google Scholar 

  14. Sterner DE, Berger SL . Acetylation of histones and transcription related factors. Microbiol. Mol Biol Rev 2000; 64: 435–459.

    Article  CAS  Google Scholar 

  15. Doyon Y, Cote J . The highly conserved and multifunctional NuA4 HAT complex. Curr Opin Genet Dev 2004; 14: 147–154.

    Article  CAS  PubMed  Google Scholar 

  16. Ruthenburg AJ, Li H, Patel DJ, Allis CD . Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 2007; 8: 983–994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hu Y, Fisher JB, Koprowski S, McAllister D, Kim MS, Lough J . Homozyous disruption of Tip60 gene causes early embryonic lethality. Dev Dyn 2009; 238: 2912–2921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gorrini C, Squatrito M, Luise C, Syed N, Perna D, Wark L et al. Tip60 is a haplo- insufficient tumour suppressor required for an oncogenes induced DNA damage response. Nature 2007; 448: 1063–1067.

    Article  CAS  PubMed  Google Scholar 

  19. Sancar A, Lindsey Boltz LA, Unsal-Kacmaz K, Linn S . Molecualr mechanism of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 2004; 73: 39–85.

    Article  CAS  PubMed  Google Scholar 

  20. Jha S, Shibata E, Dutta A . Human Rvb1/Tip49 is required for the histone Acetyltransferase activity of Tip60/NuA4 and for the downregulation of phosphorylation on H2AX after DNA damage. Mol Cell Biol 2008; 28: 2690–2700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane WS et al. Acetylation of the p53 DNA binding domain regulates apoptosis induction. Mol Cell 2006; 24: 841–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tang Y, Luo J, Zhang W, Gu W . Tip60 dependent acetylation of p53 modulates the decision between cell cycle arrest and apoptosis. Mol Cell 2006; 24: 827–839.

    Article  CAS  PubMed  Google Scholar 

  23. Bhoumik A, Singha N, O’Connell MJ, Ronai ZA . Regulation of Tip60 by ATF2 modulates ATM activation. J Biol Chem 2008; 283: 17605–17614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen J, Morral N, Engel DA . Transcription releases protein VII from adenovirus chromatin. Virology 2007; 369: 411–422.

    Article  CAS  PubMed  Google Scholar 

  25. Ferrari R, Pellegrini M, Horwitz GA, Xie W, Berk AJ, Kurdistani SK . Epigenetic reprogramming by Adenovirus eIa. Science 2008; 321: 1086–1088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Horwitz GA, Zhang K, McBrian MA, Grunstein M, Kurdistani SK, Berk AJ . Adenovirus small eia alters global patterns of histone modification. Science 2008; 321: 1084–1085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ghosh MK, Harter ML . A viral mechanism for remodeling chromatin structure in G0 cells. Mol Cell 2003; 12: 255–260.

    Article  CAS  PubMed  Google Scholar 

  28. Sha J, Ghosh MK, Zhang K, Harter ML . E1A interacts with two opposing transcriptional pathways to induce quiescent cells into S phase. J Virol 2010; 84: 4050–4059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nevels M, Tauber B, Spruss T, Wolf H, Dobner T . Hit and Run transformation by adenovirus oncogenes. J Virol 2001; 75: 3089–3094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sun Y, Jiang X, Chen S, Fernandes N, Price BD . A role for the Tip60 histone Acetyltransferase in the acetylation and activation of ATM. Proc Natl Acad Sci USA 2005; 102: 13182–13187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sun Y, Xu Y, Roy K, Price BD . DNA damage induced acetylation of lysine 3016 of ATM kinase activity. Mol Cell Biol 2007; 27: 8502–8509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kusch T, Florens L, Macdonald WH, Swanson SK, Glaser RL, Yates JR et al. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science 2004; 306: 2084–2087.

    Article  CAS  PubMed  Google Scholar 

  33. Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ et al. Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double strand breaks. Nat Cell Biol 2006; 8: 91–99.

    Article  CAS  PubMed  Google Scholar 

  34. Sapountzi V, Logan IR, Robson CN . Cellular functions of Tip60. Int J Biochem Cell Biol 2006; 38: 1496–1436.

    Article  CAS  PubMed  Google Scholar 

  35. Squatrito M, Gorrini C, Amati B . Tip60 in DNA damage response and growth control: many tricks in one HAT. Trends Cell Biol 2006; 16: 433–442.

    Article  CAS  PubMed  Google Scholar 

  36. Ikura T, Tashiro S, Kakino A, Shima H, Jacob N, Amunugama R et al. DNA damage dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Mol Cell Biol 2007; 27: 7028–7040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Karen KA, Hearing P . Adenovirus core protein VII protects viral genome from a DNA damage response at early times after infection. J Virol 2011; 85: 4135–4142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Col E, Caron C, Chable-Bessia C, Legube G, Gazzeri S, Komatsu Y et al. HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses. EMBO J 2005; 24: 2634–2645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li R, Zhu J, Xie Z, Liao G, Liu J, Chen MR et al. Conserved Herpesvirus kinases target the DNA damage pathway and Tip60 histone acetyltransferase to promote virus replication. Cell Host Microbe 2011; 10: 390–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shamay M, Liu J, Li R, Liao G, Shen L, Greenway M et al. A protein array screen for Kaposi’s sarcoma associated Herpesvirus LANA interactors link LANA to Tip60, PP2A activity, and telomere shortening. J Virol 2012; 86: 5179–5191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Johnson JS, Osheim YN, Xue Y, Emanuel MR, Lewis PW, Bankovich A et al. Adenovirus protein VII condenses DNA, represses transcription and associate with transcriptional activator EIA. J Virol 2004; 78: 6459–6468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zantema A, Fransen JA, Davis-olivier A, Ramaekers FC, Vooijs GP, Deleys B et al. Localization of the EIB proteins of adenovirus 5 in transformed cells as revealed by interaction with monoclonal antibodies. Virology 1985; 142: 44–58.

    Article  CAS  PubMed  Google Scholar 

  43. Marton MJ, Bain SB, Ornelles DA, Shenk T . The adenovirus E4 17kilodalton protein complexes with the cellular transcription factor E2F, altering its DNA binding properties and stimulating EIA independent accumulation of E2 mRNA. J Virol 1990; 64: 2345–2359.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Barker DD, Berk AJ . Adenovirus proteins from both E1B reading frames are required for the transformation of rodent cells by viral infection and DNA transfection. Virology 1987; 156: 107–121.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the members of Dutta laboratory for lively discussions and helpful comments. This work was supported by RO1 GM084465 to AD. AG was supported by US army Postdoctoral fellowship for breast cancer research DOD-W81XWH1110687.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, Charlottesville, VA, USA

    A Gupta, S Jha & A Dutta

  2. Department of Microbiology, University of Virginia, School of Medicine, Charlottesville, VA, USA

    D A Engel

  3. Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    D A Ornelles

Authors
  1. A Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Jha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D A Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D A Ornelles
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Dutta.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gupta, A., Jha, S., Engel, D. et al. Tip60 degradation by adenovirus relieves transcriptional repression of viral transcriptional activator EIA. Oncogene 32, 5017–5025 (2013). https://doi.org/10.1038/onc.2012.534

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.534

Keywords

This article is cited by

Search

Advanced search

Quick links