The Werner syndrome helicase is a cofactor for HIV-1 long terminal repeat transactivation and retroviral replication.
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.
Sharma
Anima
A
Laboratory of Molecular Virology, Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275-0376, USA.
Awasthi
Soumya
S
Harrod
Carolyn K
CK
Matlock
Elizabeth F
EF
Khan
Saiqa
S
Xu
Louisa
L
Chan
Stephanie
S
Yang
Helen
H
Thammavaram
Charu K
CK
Rasor
Randall A
RA
Burns
Dennis K
DK
Skiest
Daniel J
DJ
Van Lint
Carine
C
Girard
Anne-Marie
AM
McGee
Monnie
M
Monnat
Raymond J
RJ
Harrod
Robert
R
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
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