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首页> 外文期刊>Molecular and Cellular Biology >Human T-Cell Leukemia Virus Type 1 Tax Requires Direct Access to DNA for Recruitment of CREB Binding Protein to the Viral Promoter
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Human T-Cell Leukemia Virus Type 1 Tax Requires Direct Access to DNA for Recruitment of CREB Binding Protein to the Viral Promoter

机译：人类T细胞白血病病毒1型税需要直接获取DNA以将CREB结合蛋白招募至病毒启动子

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Efficient human T-cell leukemia virus type 1 (HTLV-1) replication and viral gene expression are dependent upon the virally encoded oncoprotein Tax. To activate HTLV-1 transcription, Tax interacts with the cellular DNA binding protein cyclic AMP-responsive element binding protein (CREB) and recruits the coactivator CREB binding protein (CBP), forming a nucleoprotein complex on the three viral cyclic AMP-responsive elements (CREs) in the HTLV-1 promoter. Short stretches of dG-dC-rich (GC-rich) DNA, immediately flanking each of the viral CREs, are essential for Tax recruitment of CBP in vitro and Tax transactivation in vivo. Although the importance of the viral CRE-flanking sequences is well established, several studies have failed to identify an interaction between Tax and the DNA. The mechanistic role of the viral CRE-flanking sequences has therefore remained enigmatic. In this study, we used high resolution methidiumpropyl-EDTA iron(II) footprinting to show that Tax extended the CREB footprint into the GC-rich DNA flanking sequences of the viral CRE. The Tax-CREB footprint was enhanced but not extended by the KIX domain of CBP, suggesting that the coactivator increased the stability of the nucleoprotein complex. Conversely, the footprint pattern of CREB on a cellular CRE lacking GC-rich flanking sequences did not change in the presence of Tax or Tax plus KIX. The minor-groove DNA binding drug chromomycin A3 bound to the GC-rich flanking sequences and inhibited the association of Tax and the Tax-CBP complex without affecting CREB binding. Tax specifically cross-linked to the viral CRE in the 5′-flanking sequence, and this cross-link was blocked by chromomycin A3. Together, these data support a model where Tax interacts directly with both CREB and the minor-groove viral CRE-flanking sequences to form a high-affinity binding site for the recruitment of CBP to the HTLV-1 promoter.
机译：高效的1型人类T细胞白血病病毒（HTLV-1）复制和病毒基因表达取决于病毒编码的癌蛋白Tax。为了激活HTLV-1转录，Tax与细胞DNA结合蛋白环状AMP响应元件结合蛋白（CREB）相互作用，并募集共激活剂CREB结合蛋白（CBP），在三个病毒环状AMP响应元件上形成核蛋白复合物（ CREs）。短链的富含dG-dC（富含GC）的DNA，立即位于每个病毒CRE的侧面，对于体外CBP的Tax募集和体内的Tax反激活是必不可少的。尽管病毒CRE侧翼序列的重要性已得到公认，但一些研究未能鉴定出Tax和DNA之间的相互作用。因此，病毒CRE侧翼序列的机械作用仍然是令人困惑的。在这项研究中，我们使用了高分辨率的甲基丙基丙基-EDTA铁（II）足迹，以表明Tax将CREB足迹扩展到了病毒CRE的富含GC的DNA侧翼序列中。通过CBP的KIX域，Tax-CREB足迹得以增强，但并未延长，这表明该共激活因子提高了核蛋白复合物的稳定性。相反，在存在Tax或Tax plus KIX的情况下，CREB在缺少富含GC的侧翼序列的细胞CRE上的足迹模式不会改变。次要凹槽DNA结合药物嗜铬霉素A 3 与富含GC的侧翼序列结合，并抑制了Tax和Tax-CBP复合物的缔合，而不会影响CREB的结合。在5'侧翼序列中，tax特异性地与病毒CRE交联，而这种交联被嗜铬菌素A 3 阻断。总之，这些数据支持一个模型，其中Tax与CREB和次要槽病毒CRE侧翼序列直接相互作用，形成一个高亲和力结合位点，用于将CBP募集到HTLV-1启动子。

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