Sharma Neelam, Nyborg Jennifer K
Department of Biochemistry and Molecular Biology, Campus Box 1870, Colorado State University, Fort Collins, CO 80523, USA.
Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):7959-63. doi: 10.1073/pnas.0800534105. Epub 2008 Jun 3.
The human T cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma. The multifunctional virally encoded oncoprotein Tax is responsible for malignant transformation and potent activation of HTLV-1 transcription. Tax, in complex with phosphorylated cAMP response element binding protein (pCREB), strongly recruits the cellular coactivators CREB binding protein (CBP)/p300 to the viral promoter concomitant with transcriptional activation. Although the mechanism of activator/coactivator-mediated transcriptional activation is poorly understood, the recruitment of CBP/p300 by regulatory factors appears to function, in part, by promoting changes in chromatin architecture that are permissive to transcriptional activation. Here, we show that CBP/p300 recruitment promotes histone acetylation and eviction of the histone octamer from the chromatin-assembled HTLV-1 promoter template in vitro. Nucleosome disassembly is strictly acetyl-CoA dependent and is not linked to ATP utilization. We find that the histone chaperone, nucleosome assembly protein 1 (NAP1), cooperates with CBP/p300 in eviction of the acetylated histones from the chromatin template. These findings reveal a unique mechanism in which the DNA-bound Tax/pCREB complex recruits CBP/p300, and together with NAP1, the coactivators cooperate to dramatically reduce nucleosome occupancy at the viral promoter in an acetylation-dependent and transcription-independent fashion.
人类T细胞白血病病毒1型（HTLV-1）是成人T细胞白血病/淋巴瘤的病原体。多功能病毒编码的癌蛋白Tax负责HTLV-1的恶性转化和转录的有效激活。Tax与磷酸化的cAMP反应元件结合蛋白（pCREB）形成复合物，在转录激活的同时，强烈地将细胞共激活因子CREB结合蛋白（CBP）/p300募集到病毒启动子上。尽管激活剂/共激活剂介导的转录激活机制尚不清楚，但调节因子对CBP/p300的募集似乎部分通过促进染色质结构的变化来发挥作用，这些变化有利于转录激活。在这里，我们表明CBP/p300的募集促进组蛋白乙酰化，并在体外从染色质组装的HTLV-1启动子模板上驱逐组蛋白八聚体。核小体拆卸严格依赖于乙酰辅酶A，与ATP利用无关。我们发现组蛋白伴侣核小体组装蛋白1（NAP1）与CBP/p300协同作用，从染色质模板上驱逐乙酰化组蛋白。这些发现揭示了一种独特的机制，即与DNA结合的Tax/pCREB复合物募集CBP/p300，并且与NAP1一起，共激活因子以乙酰化依赖和转录独立的方式协同作用，显著降低病毒启动子处的核小体占有率。
