E2F-1 regulation by an unusual DNA damage-responsive DP partner subunit
E2F-1 regulation by an unusual DNA damage-responsive DP partner subunit
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DOI：
10.1038/cdd.2010.70
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发表时间：
2011-01-01
影响因子：
12.4
通讯作者：
La Thangue, N. B.
中科院分区：
文献类型：
--
作者：
Ingram, L.;Munro, S.;La Thangue, N. B.
E2 F活性通过与E2 F-1亚基结合而受到视网膜母细胞瘤蛋白（pRb）的负调节。在E2 F异二聚体中，DP蛋白是允许适当细胞周期进展的E2 F伴侣亚基。与其他DP蛋白相比，DP-4家族的最新成员下调E2 F活性。在这项研究中，我们报告了DP-4在DNA损伤反应过程中调节E2 F-1活性的意想不到的作用。具体而言，DP-4在DNA损伤的细胞中被诱导，在此之后，它作为非DNA结合E2 F-1/DP-4复合物与E2 F-1结合。因此，在细胞中消耗DP-4恢复E2 F-1活性，这与染色质结合的E2 F-1、E2 F-1靶基因表达和相关凋亡水平的增加相一致。DP-4的突变分析突出了E2 F-1活性阴性对照所需的DNA结合结构域外的C-末端区域。我们的研究结果定义了一个新的途径，它的作用独立于pRb，并通过一个生化独特的机制，参与负调控E2 F-1活性。Cell Death and Differentiation（2011）18，122-132; doi：10.1038/cdd.2010.70; 2010年6月18日在线发表
E2F activity is negatively regulated by retinoblastoma protein (pRb) through binding to the E2F-1 subunit. Within the E2F heterodimer, DP proteins are E2F partner subunits that allow proper cell cycle progression. In contrast to the other DP proteins, the newest member of the family, DP-4, downregulates E2F activity. In this study we report an unexpected role for DP-4 in regulating E2F-1 activity during the DNA damage response. Specifically, DP-4 is induced in DNA-damaged cells, upon which it binds to E2F-1 as a non-DNA-binding E2F-1/DP-4 complex. Consequently, depleting DP-4 in cells re-instates E2F-1 activity that coincides with increased levels of chromatin-bound E2F-1, E2F-1 target gene expression and associated apoptosis. Mutational analysis of DP-4 highlighted a C-terminal region, outside the DNA-binding domain, required for the negative control of E2F-1 activity. Our results define a new pathway, which acts independently of pRb and through a biochemically distinct mechanism, involved in negative regulation of E2F-1 activity. Cell Death and Differentiation (2011) 18, 122-132; doi: 10.1038/cdd.2010.70; published online 18 June 2010