Preferred binding of gain-of-function mutant p53 to bidirectional promoters with coordinated binding of ETS1 and GABPA to multiple binding sites.
Preferred binding of gain-of-function mutant p53 to bidirectional promoters with coordinated binding of ETS1 and GABPA to multiple binding sites.
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DOI：
10.18632/oncotarget.1708
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发表时间：
2014-01-30
期刊：
影响因子：
--
通讯作者：
Windle B
中科院分区：
文献类型：
--
作者：
Vaughan CA;Deb SP;Deb S;Windle B
功能获得突变型p53被认为部分通过结合与介导肿瘤发生的基因的启动子结合的转录因子来诱导基因表达。我们通过使用ChIP-Seq绘制p53 R273 H的人类基因组结合位点来研究突变型p53结合的机制，并显示它们定位于ETS DNA序列基序以及与ETS 1和GABPA结合的位置，无论是在启动子内还是在启动子远端。引人注目的是，p53 R273 H表现出统计学上显著的和实质性的结合双向启动子，这是丰富的反向重复ETS DNA序列基序。p53 R273 H表现出与具有更高数量的ETS基序的启动子结合的概率的指数增加。ETS 1和GABPA都显示出与具有更高数量的ETS基序的启动子结合的概率增加。然而，尽管p53 R273 H和ETS 1结合的可能性增加，但结合信号没有增加，表明每个启动子结合的ETS 1和p53 R273 H蛋白的数量是有限的。相比之下，GABPA确实表现出结合信号的增加，每个启动子具有更高数量的ETS基序。对启动子内反向的ETS基序对之间的距离以及p53 R273 H、ETS 1和GABPA的结合进行分析，显示了这三种蛋白质结合的新型协调。ETS 1和p53 R273 H都表现出对具有面对面和背靠背方向的远距离间隔ETS基序的结合启动子的偏好，以及对具有紧密间隔ETS基序的启动子的低结合偏好。GABPA表现出相反的结合模式，更喜欢结合启动子与紧密间隔的ETS基序。ETS基序之间的螺旋相位的分析表明，ETS 1和p53 R273 H表现出低偏好的结合启动子与ETS基序在同一面的DNA螺旋。我们提出了一个模型的结合ETS 1和p53 R273 H，其中两个倒ETS基序的环状DNA螺旋并列ETS 1结合作为一个同源二聚体，与p53 R273 H结合ETS 1。我们建议，这种DNA环和蛋白质结合复合物的形成，防止额外的结合ETS 1和p53 R273 H蛋白质的其他近端结合位点。
Gain-of-function mutant p53 is thought to induce gene expression in part by binding transcription factors bound to promoters for genes that mediate oncogenesis. We investigated the mechanism of mutant p53 binding by mapping the human genomic binding sites for p53 R273H using ChIP-Seq and showed them to localize to ETS DNA sequence motifs and locations with ETS1 and GABPA binding, both within promoters and distal to promoters. Strikingly, p53 R273H showed statistically significant and substantial binding to bidirectional promoters, which are enriched for inverted repeated ETS DNA sequence motifs. p53 R273H exhibited an exponential increase in probability of binding promoters with a higher number of ETS motifs. Both ETS1 and GABPA also showed an increase in the probability of binding to promoters with a higher number of ETS motifs. However, despite this increase in probability of binding by p53 R273H and ETS1, there was no increase in the binding signal, suggesting that the number of ETS1 and p53 R273H proteins bound per promoter is being limited. In contrast, GABPA did exhibit an increase in binding signal with higher numbers of ETS motifs per promoter. Analysis of the distance between inverted pairs of ETS motifs within promoters and binding by p53 R273H, ETS1 and GABPA, showed a novel coordination of binding for the three proteins. Both ETS1 and p53 R273H exhibited preference for binding promoters with distantly spaced ETS motifs in face-to-face and back-to-back orientations, and low binding preference to promoters with closely spaced ETS motifs. GABPA exhibited the inverse pattern of binding by preferring to bind promoters with closely spaced ETS motifs. Analysis of the helical phase between ETS motifs showed that ETS1 and p53 R273H exhibited a low preference for binding promoters with ETS motifs on the same face of the DNA helix. We propose a model for the binding of ETS1 and p53 R273H in which two inverted ETS motifs on a looped DNA helix are juxtaposed for ETS1 binding as a homodimer, with p53 R273H bound to ETS1. We propose that the formation of this DNA loop and protein-bound complex prevents additional binding of ETS1 and p53 R273H proteins to other proximal binding sites.
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影响因子：
4.5
作者：
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通讯作者：
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