Menon Balaraj B, Sarma Nayan J, Pasula Satish, Deminoff Stephen J, Willis Kristine A, Barbara Kellie E, Andrews Brenda, Santangelo George M
Department of Biological Sciences, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5749-54. doi: 10.1073/pnas.0501768102. Epub 2005 Apr 7.
The recruitment model for gene activation presumes that DNA is a platform on which the requisite components of the transcriptional machinery are assembled. In contrast to this idea, we show here that Rap1/Gcr1/Gcr2 transcriptional activation in yeast cells occurs through a large anchored protein platform, the Nup84 nuclear pore subcomplex. Surprisingly, Nup84 and associated subcomplex components activate transcription themselves in vivo when fused to a heterologous DNA-binding domain. The Rap1 coactivators Gcr1 and Gcr2 form an important bridge between the yeast nuclear pore complex and the transcriptional machinery. Nucleoporin activation may be a widespread eukaryotic phenomenon, because it was first detected as a consequence of oncogenic rearrangements in acute myeloid leukemia and related syndromes in humans. These chromosomal translocations fuse a homeobox DNA-binding domain to the human homolog (hNup98) of a transcriptionally active component of the yeast Nup84 subcomplex. We conclude that Rap1 target genes are activated by moving to contact compartmentalized nuclear assemblages, rather than through recruitment of the requisite factors to chromatin by means of diffusion. We term this previously undescribed mechanism "reverse recruitment" and discuss the possibility that it is a central feature of eukaryotic gene regulation. Reverse recruitment stipulates that activators work by bringing the DNA to an nuclear pore complex-tethered platform of assembled transcriptional machine components.
基因激活的招募模型假定DNA是一个平台，转录机制的必要组件在其上组装。与这一观点相反，我们在此表明酵母细胞中的Rap1/Gcr1/Gcr2转录激活是通过一个大型锚定蛋白平台——Nup84核孔亚复合体发生的。令人惊讶的是，当与异源DNA结合结构域融合时，Nup84及相关亚复合体组件在体内自身就能激活转录。Rap1共激活因子Gcr1和Gcr2在酵母核孔复合体与转录机制之间形成了一个重要的桥梁。核孔蛋白激活可能是一种广泛存在的真核生物现象，因为它最初是在急性髓系白血病及人类相关综合征的致癌重排中被检测到的。这些染色体易位将一个同源框DNA结合结构域与酵母Nup84亚复合体转录活性组件的人类同源物（hNup98）融合。我们得出结论，Rap1靶基因是通过移动至与区室化的核组装体接触而被激活的，而不是通过将必要因子扩散募集到染色质上来激活。我们将这种以前未描述的机制称为“反向募集”，并讨论了它可能是真核基因调控核心特征的可能性。反向募集规定激活因子的作用方式是将DNA带到由组装好的转录机器组件与核孔复合体相连的平台上。
