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

Abstract

(1) have demonstrated that WRN contributes to general RNA pol II 4 -dependent transcription, although its mechanism remains unclear. Interestingly, these authors found that a 27-amino acid direct-repeat sequence strongly activated transcription in yeast two-hybrid experiments, independent of WRN 3Ј 3 5Ј DNA helicase activity (1) (Fig. 1A) suggesting that WRN interacts with cellular factors to modulate RNA pol II-dependent transcription. The WRN protein localizes to nucleoli and the nucleoplasm of transcriptionally active cells (1, 2). Moreover, Laine et al. (3) have shown that WRN stimulates topoisomerase I DNA-unwinding activity that could influence cellular transcription. The yeast WRN homologue, SGS1, also participates in DNA replication and RNA pol I-dependent transcription (4), and the WRN helicase enhances RNA pol I-dependent transcription of ribosomal RNA (5).In the present study, we have investigated whether WRN contributes to HIV-1 LTR transactivation and retroviral replication. The HIV-1 LTR contains upstream enhancer elements (e.g. NF-B and SP1) that synergize with the transactivator protein, Tat, bound to TAR-RNA, to promote retroviral gene expression in HIV-1-infected tissues, macrophages/monocytes, and CD4 ϩ T-lymphocytes (6 -17). The mechanism by which Tat/TAR-RNA complexes regulate transcription from the HIV-1 LTR involves the concerted recruitment of a plethora of cellular factors, including p300/CREB-binding protein (p300/CBP) (18 -25), [26][27][28][29][30], P-TEFb (30 -33), SET7/SET9 methyltransferases (34), SIRT1 (35), the Brm component of the SWI/SNF chromatin-remodeling com-

The Werner Protein Acts as a Coactivator of Nuclear Factor κB (NF-κB) on HIV-1 and Interleukin-8 (IL-8) Promoters

“…For immortalized WRN Ϫ/Ϫ WS fibroblasts, Sharma et al (11) concluded that WRN participates in the recruitment of PCAF/P-TEFb-containing transcription complexes to HIV-1 LTR. Taken together with their findings, the RelA/p50 activation-mediated increase in association of WRN to the LTR is expected to result in enhanced recruitment of the PCAF/PTEFb-containing transcription complexes.…”

“…Sequence-WRN was previously reported to be tethered on the HIV-1 LTR in the presence of the viral transactivating Tat protein (11). However, the mechanisms underlying WRN recruitment to LTR are still unknown (11).…”

“…However, the mechanisms underlying WRN recruitment to LTR are still unknown (11). A previous study showed that LTR is occupied by the repressive p50/p50 homodimer in an unstimulated state, which is replaced by the RelA/p50 heterodimer after TNF-␣ stimulation (15).…”

“…However, only scarce information is available about WRN target gene specificity and the mechanism by which WRN controls transcriptional activation of those genes, either directly or indirectly. Sharma et al (11) reported a probable participation of WRN in retroviral transactivation and replication. In their study, WRN was reported to interact and cooperate with the Tat HIV-1 trans-activating protein to activate HIV-1 long terminal repeat (LTR) by recruiting histone acetyltransferase.…”

Progress and prospects: RNA-based therapies for treatment of HIV infection

“…4 Not surprisingly, drugs against cellular cofactors have high toxicity, but are still being pursued as options in the event of failure of HAART chemotherapy. Other recently identified cofactors in activation of HIV transcription include the Werner's syndrome helicase 5 and p90 ribosomal S6 kinase 2 (RSK2). 6 There has also been a great deal of interest regarding the TAR-binding protein (TRBP) and its effects on HIV replication.…”