Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements.
Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements.
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DOI：
10.1371/journal.pone.0022911
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Schindler D
中科院分区：
文献类型：
--
作者：
Meier D;Schindler D
范可尼贫血 (FA) 基因家族是复杂蛋白质网络中的最新成员，可响应并修复人类基因组中某些类型的 DNA 损伤。由于人们对这组新基因在 DNA 水平上的调控知之甚少，我们对构成 FA 核心复合体的八个基因（FANCA、B、C、E、F、G、L 和 M）的启动子进行了表征。这些基因的启动子显示出管家基因的特征属性，例如高GC含量和CpG岛、缺乏TATA盒和低保守性。启动子以单向方式发挥作用，并且在其最活跃的区域中，其强度与我们的报告质粒中的 SV40 启动子相当。它们还以独特的转录起始位点（TSS）为标志。在每个启动子的 5' 区域，我们鉴定了一个能够单独负向调节 HeLa 和 HEK 293 细胞中启动子活性的区域。启动子序列的中央和3'区包含一些常见和罕见转录因子的结合位点，包括STAT、SMAD、E2F、AP1和YY1，这表明可能与几个已建立的调控途径存在交叉连接。电泳迁移率变动分析和 siRNA 实验证实了 TGF-β 和 JAK/STAT 途径的主要成员与 FA 核心复合物的成员之间存在共同的调节反应。尽管启动子不是很保守，但它们共享区域和序列特异性调控基序和转录因子结合位点（TBF），并且我们鉴定了这些启动子的二分性质。这些结果支持基于 FA 核心复合体基因共同进化的假设，该基因已扩展至包括其启动子。
The Fanconi anemia (FA) gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M) that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS). In the 5′ region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3′ regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-β and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs), and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters.
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