Department of Molecular Biology, Biomedical Center Munich, Faculty of Medicine, Ludwig-Maximilians University, Großhaderner Strasse 9, 82152 Planegg-Martinsried, Germany.
Department of Pharmacy, Institute of Chemical Epigenetics, Ludwig-Maximilians University, Butenandtstraße 5-13, 81377 München, Germany.
Nucleic Acids Res. 2023 Oct 13;51(18):9629-9642. doi: 10.1093/nar/gkad681.
The use of synthetic chemicals to selectively interfere with chromatin and the chromatin-bound proteome represents a great opportunity for pharmacological intervention. Recently, synthetic foldamers that mimic the charge surface of double-stranded DNA have been shown to interfere with selected protein-DNA interactions. However, to better understand their pharmacological potential and to improve their specificity and selectivity, the effect of these molecules on complex chromatin needs to be investigated. We therefore systematically studied the influence of the DNA mimic foldamers on the chromatin-bound proteome using an in vitro chromatin assembly extract. Our studies show that the foldamer efficiently interferes with the chromatin-association of the origin recognition complex in vitro and in vivo, which leads to a disturbance of cell cycle in cells treated with foldamers. This effect is mediated by a strong direct interaction between the foldamers and the origin recognition complex and results in a failure of the complex to organise chromatin around replication origins. Foldamers that mimic double-stranded nucleic acids thus emerge as a powerful tool with designable features to alter chromatin assembly and selectively interfere with biological mechanisms.
使用合成化学物质有选择性地干扰染色质和染色质结合的蛋白质组代表了药物干预的巨大机会。最近，模拟双链 DNA 电荷表面的合成折叠体已被证明可以干扰选定的蛋白-DNA 相互作用。然而，为了更好地了解它们的药理潜力并提高它们的特异性和选择性，需要研究这些分子对复杂染色质的影响。因此，我们使用体外染色质组装提取物系统地研究了 DNA 模拟折叠体对染色质结合蛋白质组的影响。我们的研究表明，折叠体有效地干扰了体外和体内的原点识别复合物与染色质的结合，导致用折叠体处理的细胞中的细胞周期紊乱。这种效应是由折叠体与原点识别复合物之间的强烈直接相互作用介导的，导致该复合物无法围绕复制起点组织染色质。因此，模拟双链核酸的折叠体作为一种具有可设计特征的强大工具出现，可以改变染色质组装并选择性地干扰生物机制。
