Nucleic Acids Research Advance Access originally published online on August 20, 2009
Nucleic Acids Research 2009 37(18):6008-6018; doi:10.1093/nar/gkp673
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nucleic Acids Research, 2009, Vol. 37, No. 18 6008-6018
© The Author 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses?by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gene Regulation, Chromatin and Epigenetics |
Uracil DNA Glycosylase 2 negatively regulates HIV-1 LTR transcription
1Université Montpellier 1, Centre d’études d’agents Pathogènes et Biotechnologies pour la Santé (CPBS), 2CNRS, UMR 5236, CPBS, F-34965 Montpellier and 3Université Montpellier 2, CPBS, F-34095 Montpellier, France
*To whom correspondence should be addressed. Tel: +33 467600350; Fax: +33 467604420; Email: laurence.briant{at}univ-montp1.fr
Received May 14, 2008. Revised July 27, 2009. Accepted July 30, 2009.
Numerous cellular factors belonging to the DNA repair machineries, including RAD18, RAD52, XPB and XPD, have been described to counteract human immunodeficiency virus type 1 (HIV-1) replication. Recently, Uracil DNA glycosylase 2 (UNG2), a major determinant of the uracil base excision repair pathway, was shown to undergo rapid proteasome-dependent degradation following HIV-1 infection. However, the specific role of intracellular UNG2 depletion during the course of HIV-1 infection is not clearly understood. Our study shows for the first time that overexpression of UNG2 inhibits HIV-1 replication. We demonstrate that this viral inhibition is correlated with a marked decrease in transcription efficiency as shown by monitoring HIV-1 LTR promoter activity and quantification of HIV-1 RNA levels. Interestingly, UNG2 inhibits LTR activity when stimulated by Tat transactivator or TNF
, while barely affected using Phorbol ester activation. Mutational analysis of UNG2 indicates that antiviral activity may require the integrity of the UNG2 catalytic domain. Altogether, our data indicate that UNG2 is likely to represent a new host defense factor specifically counteracted by HIV-1 Vpr. The molecular mechanisms involved in the UNG2 antiviral activity still remain elusive but may rely on the sequestration of specific cellular factor(s) critical for viral transcription.
Present addresses: David Fenard, GENETHON, 1bis rue de l’Internationale—BP60, 91002 Evry Cedex, France. Laurent Houzet, Molecular Virology Section, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892-0460, USA.