title: The Werner syndrome helicase is a cofactor for HIV-1 long terminal repeat transactivation and retroviral replication.
abstract: 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.
authors.affiliation: Laboratory of Molecular Virology, Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275-0376, USA.
authors.forename: Anima
authors.initials: A
authors.lastname: Sharma
authors.forename: Soumya
authors.initials: S
authors.lastname: Awasthi
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Harrod
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Matlock
authors.forename: Saiqa
authors.initials: S
authors.lastname: Khan
authors.forename: Louisa
authors.initials: L
authors.lastname: Xu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chan
authors.forename: Helen
authors.initials: H
authors.lastname: Yang
authors.forename: Charu K
authors.initials: CK
authors.lastname: Thammavaram
authors.forename: Randall A
authors.initials: RA
authors.lastname: Rasor
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Burns
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Skiest
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Girard
authors.forename: Monnie
authors.initials: M
authors.lastname: McGee
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Monnat
authors.forename: Robert
authors.initials: R
authors.lastname: Harrod
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D005347:Fibroblasts / Q000378:metabolism; D015696:Gene Products, tat / Q000378:metabolism; D016325:HIV Long Terminal Repeat; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008954:Models, Biological; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D053484:RecQ Helicases / Q000378:metabolism / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014779:Virus Replication; D014898:Werner Syndrome / Q000201:enzymology; D000071657:Werner Syndrome Helicase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D018797:Cell Cycle Proteins; D004265:DNA Helicases; D005090:Exodeoxyribonucleases; D015696:Gene Products, tat; D051548:Histone Acetyltransferases; D042925:Positive Transcriptional Elongation Factor B; D053484:RecQ Helicases; D014157:Transcription Factors; D000071657:Werner Syndrome Helicase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C098785:WRN protein, human