National Laboratory for Condensed Matter Physics and Key Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Biochemistry. 2021 Feb 23;60(7):494-499. doi: 10.1021/acs.biochem.1c00014. Epub 2021 Feb 11.
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.
候选抗癌药物 curaxin 可以插入 DNA 碱基对，有效地抑制各种癌症的生长。然而，curaxin 如何改变基因组 DNA 结构并影响关键蛋白质的 DNA 结合特性仍有待阐明。在这里，我们首次通过单分子磁镊实验表明，curaxin CBL0137 能够强烈稳定 DNA 双链之间的相互作用，同时降低 DNA 弯曲和扭转刚性。更重要的是，我们发现 CBL0137 极大地损害了 CTCF 的结合，但促进了 FACT 在 DNA 上的捕获。我们揭示了 CBL0137 夹在 DNA 双螺旋上，这可能在复制和转录过程中为 DNA 解旋产生巨大的障碍，并导致 CTCF 和 FACT 在 DNA 上的独特结合反应。我们的工作为 CBL0137 在核酸水平上的抗癌机制提供了新的力学见解。
