HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 16, 12048-12057, April 20, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/16/12048    most recent M608104200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sharma, A. Articles by Harrod, R. Search for Related Content PubMed PubMed Citation Articles by Sharma, A. Articles by Harrod, R. Social Bookmarking                      What's this?

The Werner Syndrome Helicase Is a Cofactor for HIV-1 Long Terminal Repeat Transactivation and Retroviral Replication^*

Anima Sharma¹, Soumya Awasthi¹, Carolyn K. Harrod, Elizabeth F. Matlock, Saiqa Khan, Louisa Xu, Stephanie Chan, Helen Yang, Charu K. Thammavaram, Randall A. Rasor, Dennis K. Burns, Daniel J. Skiest^¶, Carine Van Lint^||2, Anne-Marie Girard^**, Monnie McGee, Raymond J. Monnat, Jr., and Robert Harrod³

From the Laboratory of Molecular Virology, Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275-0376, the Division of Neuropathology, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9072, the ^¶Division of Infectious Diseases, HIV Section, Baystate Medical Center, Springfield, Massachusetts 01109, the ^||Laboratoire de Virologie Moléculaire, Service de Chimie Biologique, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Rue des Profs Jeener et Brachet, 12, 6041 Gosselies, Belgium, the ^**Center for Gene Research and Biotechnology, Oregon State University, Corvallis, Oregon 97331, the Department of Statistical Science, Southern Methodist University, Dallas, Texas 75275-0332, and the Department of Pathology, University of Washington, Seattle, Washington 98195-7705

The Werner syndrome helicase (WRN) participates in DNA replication, double strand break repair, telomere maintenance, and p53 activation. Mutations of wrn cause Werner syndrome (WS), an autosomal recessive premature aging disorder associated with cancer predisposition, atherosclerosis, and other aging related symptoms. Here, we report that WRN is a novel cofactor for HIV-1 replication. Immortalized human WRN^-/- WS fibroblasts, lacking a functional wrn gene, are impaired for basal and Tat-activated HIV-1 transcription. Overexpression of wild-type WRN transactivates the HIV-1 long terminal repeat (LTR) in the absence of Tat, and WRN cooperates with Tat to promote high-level LTR transactivation. Ectopic WRN induces HIV-1 p24^Gag production and retroviral replication in HIV-1-infected H9_HIV-1IIIB lymphocytes. A dominant-negative helicase-minus mutant, WRN_K577M, inhibits LTR transactivation and HIV-1 replication. Inhibition of endogenous WRN, through co-expression of WRN_K577M, diminishes recruitment of p300/CREB-binding protein-associated factor (PCAF) and positive transcription elongation factor b (P-TEFb) to Tat/transactivation response-RNA complexes, and immortalized WRN^-/- WS fibroblasts exhibit comparable defects in recruitment of PCAF and P-TEFb to the HIV-1 LTR. Our results demonstrate that WRN is a novel cellular cofactor for HIV-1 replication and suggest that the WRN helicase participates in the recruitment of PCAF/P-TEFb-containing transcription complexes. WRN may be a plausible target for antiretroviral therapy.

Received for publication, August 23, 2006 , and in revised form, January 31, 2007.

^* This work was supported in part by the Department of Biological Sciences, Southern Methodist University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Maître de Recherches from the Fonds National de la Recherche Scientifique (Belgium) and supported by the Fonds National de la Recherche Scientifique, Televie, Free University of Brussels (ARC), Internationale Brachet Stiftung, CGRI-INSERM cooperation, the Theyskens-Mineur Foundation, Region Wallone-Commission Europeenne FEDER, and the Agence Nationale de Recherches sur le SIDA (ANRS, France).

³ To whom correspondence should be addressed: 6501 Airline Dr., 334-DLS, Dallas, TX 75275-0376. Tel.: 214-768-3864; Fax: 214-768-3955; E-mail: rharrod{at}mail.smu.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?