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

• Published in: The Journal of biological chemistry Vol. 282; no. 16; pp. 12048 - 12057
• Main Authors: Sharma, Anima, Awasthi, Soumya, Harrod, Carolyn K., Matlock, Elizabeth F., Khan, Saiqa, Xu, Louisa, Chan, Stephanie, Yang, Helen, Thammavaram, Charu K., Rasor, Randall A., Burns, Dennis K., Skiest, Daniel J., Van Lint, Carine, Girard, Anne-Marie, McGee, Monnie, Monnat, Raymond J., Harrod, Robert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-04-2007; American Society for Biochemistry and Molecular Biology
• Subjects: Cell Cycle Proteins - metabolism; DNA Helicases - metabolism; Exodeoxyribonucleases; Fibroblasts - metabolism; Gene Products, tat - metabolism; HeLa Cells; Histone Acetyltransferases - metabolism; HIV Long Terminal Repeat; Human immunodeficiency virus 1; Humans; Lymphocytes - metabolism; Models, Biological; p300-CBP Transcription Factors; Positive Transcriptional Elongation Factor B - metabolism; RecQ Helicases - metabolism; RecQ Helicases - physiology; Retroviridae - genetics; Transcription Factors - metabolism; Transcriptional Activation; Virus Replication; Werner Syndrome - enzymology; Werner Syndrome Helicase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M608104200

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 p24Gag production and retroviral replication in HIV-1-infected H9HIV-1IIIB lymphocytes. A dominant-negative helicase-minus mutant, WRNK577M, inhibits LTR transactivation and HIV-1 replication. Inhibition of endogenous WRN, through co-expression of WRNK577M, 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.