Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd 204A, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):563-8. doi: 10.1073/pnas.1016020107. Epub 2010 Dec 22.
The tumor suppressor p53 slides along DNA while searching for its cognate site. Central to this process is the basic C-terminal domain, whose regulatory role and its coordination with the core DNA-binding domain is highly debated. Here we use single-molecule techniques to characterize the search process and disentangle the roles played by these two DNA-binding domains in the search process. We demonstrate that the C-terminal domain is capable of rapid translocation, while the core domain is unable to slide and instead hops along DNA. These findings are integrated into a model, in which the C-terminal domain mediates fast sliding of p53, while the core domain samples DNA by frequent dissociation and reassociation, allowing for rapid scanning of long DNA regions. The model further proposes how modifications of the C-terminal domain can activate "latent" p53 and reconciles seemingly contradictory data on the action of different domains and their coordination.
肿瘤抑制因子 p53 在 DNA 上滑动以寻找其同源位点。这个过程的核心是基本的 C 端结构域,其调节作用及其与核心 DNA 结合结构域的协调作用备受争议。在这里,我们使用单分子技术来描述搜索过程,并厘清这两个 DNA 结合结构域在搜索过程中的作用。我们证明 C 端结构域能够快速迁移,而核心结构域则无法滑动,而是在 DNA 上跳跃。这些发现被整合到一个模型中,该模型认为 C 端结构域介导 p53 的快速滑动,而核心结构域通过频繁的解离和再结合来探测 DNA,从而能够快速扫描长 DNA 区域。该模型进一步提出了 C 端结构域的修饰如何激活“潜伏”的 p53,并调和了不同结构域及其协调作用的看似矛盾的数据。