Research Papers:

Human T-cell leukemia virus type-1-encoded protein HBZ represses p53 function by inhibiting the acetyltransferase activity of p300/CBP and HBO1

Diana G. Wright, Claire Marchal, Kimson Hoang, John A. Ankney, Stephanie T. Nguyen, Amanda W. Rushing, Nicholas Polakowski, Benoit Miotto and Isabelle Lemasson _

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Oncotarget. 2016; 7:1687-1706. https://doi.org/10.18632/oncotarget.6424

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Diana G. Wright1,*, Claire Marchal2,*, Kimson Hoang1, John A. Ankney1,3, Stephanie T. Nguyen1, Amanda W. Rushing1, Nicholas Polakowski1, Benoit Miotto2,4,5,6, Isabelle Lemasson1

1Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA

2Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216, CNRS, Paris, France

3Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

4INSERM, U1016, Institut Cochin, Paris, France

5CNRS, UMR8104, Paris, France

6Université Paris Descartes, Sorbonne Paris Cité, Paris, France

*These authors contributed equally to this work

Correspondence to:

Isabelle Lemasson, e-mail: [email protected]

Keywords: human T-cell leukemia virus type-1, adult T-cell leukemia, HBZ, histone acetyl transferase activity, p53

Received: July 27, 2015     Accepted: November 15, 2015     Published: November 28, 2015


Adult T-cell leukemia (ATL) is an often fatal malignancy caused by infection with the complex retrovirus, human T-cell Leukemia Virus, type 1 (HTLV-1). In ATL patient samples, the tumor suppressor, p53, is infrequently mutated; however, it has been shown to be inactivated by the viral protein, Tax. Here, we show that another HTLV-1 protein, HBZ, represses p53 activity. In HCT116 p53+/+ cells treated with the DNA-damaging agent, etoposide, HBZ reduced p53-mediated activation of p21/CDKN1A and GADD45A expression, which was associated with a delay in G2 phase-arrest. These effects were attributed to direct inhibition of the histone acetyltransferase (HAT) activity of p300/CBP by HBZ, causing a reduction in p53 acetylation, which has be linked to decreased p53 activity. In addition, HBZ bound to, and inhibited the HAT activity of HBO1. Although HBO1 did not acetylate p53, it acted as a coactivator for p53 at the p21/CDKN1A promoter. Therefore, through interactions with two separate HAT proteins, HBZ impairs the ability of p53 to activate transcription. This mechanism may explain how p53 activity is restricted in ATL cells that do not express Tax due to modifications of the HTLV-1 provirus, which accounts for a majority of patient samples.

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