Curaxin-Induced DNA Topology Alterations Trigger the Distinct Binding Response of CTCF and FACT at the Single-Molecule Level
Curaxin-Induced DNA Topology Alterations Trigger the Distinct Binding Response of CTCF and FACT at the Single-Molecule Level
复制标题
Curaxin 诱导的 DNA 拓扑结构改变在单分子水平上触发 CTCF 和 FACT 的独特结合反应
DOI：
10.1021/acs.biochem.1c00014
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发表时间：
2021-02-11
期刊：
影响因子：
2.9
通讯作者：
Chen, Ping
中科院分区：
文献类型：
--
作者：
Lu, Ke;Liu, Cuifang;Chen, Ping
候选抗癌药物curaxins可以插入DNA碱基对，有效抑制多种肿瘤的生长。然而，curaxins如何改变基因组DNA结构并影响关键蛋白的DNA结合特性仍有待阐明。在这里，我们首次通过单分子磁镊子证明curaxin CBL0137强有力地稳定了DNA双链之间的相互作用，同时降低了DNA的弯曲和扭转刚度。更重要的是，我们发现CBL0137极大地削弱了CTCF的结合，但促进了FACT在DNA上的捕获。我们发现CBL0137夹住DNA双螺旋，这可能在复制和转录过程中诱导DNA解压缩的巨大障碍，并导致CTCF和FACT在DNA上的不同结合反应。我们的工作为CBL0137在核酸水平上的抗癌机制提供了新的机械见解。
The candidate anticancer drug curaxins can insert into DNA base pairs and efficiently inhibit the growth of various cancers. However, how curaxins alter the genomic DNA structure and affect the DNA binding property of key proteins remains to be clarified. Here, we first showed that curaxin CBL0137 strongly stabilizes the interaction between the double strands of DNA and reduces DNA bending and twist rigidity simultaneously, by single-molecule magnetic tweezers. More importantly, we found that CBL0137 greatly impairs the binding of CTCF but facilitates trapping FACT on DNA. We revealed that CBL0137 clamps the DNA double helix that may induce a huge barrier for DNA unzipping during replication and transcription and causes the distinct binding response of CTCF and FACT on DNA. Our work provides a novel mechanical insight into CBL0137's anticancer mechanisms at the nucleic acid level.