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Journal of Virology, January 2009, p. 117-127, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01515-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding {triangledown}

Jennifer Hein,1 Sergei Boichuk,1 Jiaping Wu,4,{dagger} Yuan Cheng,4,{ddagger} Raimundo Freire,2 Parmjit S. Jat,3 Thomas M. Roberts,4 and Ole V. Gjoerup1*

Molecular Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213,1 Unidad de Investigacion, Hospital Universitario de Canarias, Ofra S/N, La Cuesta, 38320 Tenerife, Spain,2 Department of Neurodegenerative Diseases, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom,3 Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts 021154

Received 18 July 2008/ Accepted 3 October 2008

Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that is important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shown to lead to the induction of DNA damage response signaling, which is required for efficient viral replication. However, it was not clear if LT is sufficient to induce the damage response and, if so, what the genetic requirements and functional consequences might be. Here, we show that the expression of LT alone, without a replication origin, can induce key DNA damage response markers including the accumulation of {gamma}-H2AX and 53BP1 in nuclear foci. Other DNA damage-signaling components downstream of ATM/ATR kinases were induced, including chk1 and chk2. LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins. Stimulation of the damage response by LT depends mainly on binding to Bub1 rather than to the retinoblastoma protein. LT has long been known to stabilize p53 despite functionally inactivating it. We show that the activation of a DNA damage response by LT via Bub1 appears to play a major role in p53 stabilization by promoting the phosphorylation of p53 at Ser15. Accompanying the DNA damage response, LT induces tetraploidy, which is also dependent on Bub1 binding. Taken together, our data suggest that LT, via Bub1 binding, breaches genome integrity mechanisms, leading to DNA damage responses, p53 stabilization, and tetraploidy.

* Corresponding author. Mailing address: Hillman Cancer Center, Research Pavilion Suite 1.8, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: (412) 623-7717. Fax: (412) 623-7715. E-mail: ovg27{at}pitt.edu

{triangledown} Published ahead of print on 15 October 2008.

{dagger} Present address: Beth Israel Deaconess Medical Center, Boston, MA 02115.

{ddagger} Present address: Imclone Systems Incorporated, New York, NY 10014.

Journal of Virology, January 2009, p. 117-127, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01515-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tei, S., Saitoh, N., Funahara, T., Iida, S.-i., Nakatsu, Y., Kinoshita, K., Kinoshita, Y., Saya, H., Nakao, M. (2009). Simian virus 40 large T antigen targets the microtubule-stabilizing protein TACC2. J. Cell Sci. 122: 3190-3198 [Abstract] [Full Text]  


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