Supramolecular Coordination-Directed Reversible Regulation of Protein Activities at Epigenetic DNA Marks
Supramolecular Coordination-Directed Reversible Regulation of Protein Activities at Epigenetic DNA Marks
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表观遗传 DNA 标记处蛋白质活性的超分子配位可逆调控
DOI：
10.1021/jacs.8b09113
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
周翔
中科院分区：
文献类型：
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作者：
王少儒;Jia-Qi Wang;Bo-Shi Fu;Kun Chen;Wei Xiong;Lai Wei;卿光焱;田沺;周翔
在哺乳动物中，已经确定了5型甲状腺素（5FC），它在活跃的DNA脱甲基化中起着重要的作用，并且在表观遗传学上也很重要。对可逆调节的内化化学DNA蛋白在此标记上的相互作用。喹啉环中的氮原子与CH组重要。这些补充金属离子的调节作用是根据组合信息的。与完整的核基础相反，可以通过补充许多螯合剂来补充协调诱导的活性控制。
In mammals, 5-formylcytosine (5fC) has been identified as an important mark, which plays significant roles in active DNA demethylation and also in epigenetic regulation. It is therefore important to target this epigenetic mark as well as manipulating DNA−protein interactions at this site. A unique.feature of 5fC is the presence of a formyl group at the C-5 position. In the current study, we introduce supramolecular coordination chemistry for reversible regulation of DNA−protein interactions on this mark. We have designed and synthesized the 2-(aminooxy)-N-(quinolin-8-yl)acetamide (AQA), which functions well in selective labeling of 5fC mark. Using this feature, the association and disassociation of metal ion supplementation allow blocking and deblocking of DNA−protein interactions. In addition, we synthesized a close analogue of AQA by replacing the nitrogen atom in the quinoline ring with a CH group. Importantly, the regulatory effects of those metal ion supplementations were completely erased. On the basis of the combined information, we propose a.conformational flexibility in a side arm in response to switched coordination. In the absence of coordinating interaction, the flexible side arm probably takes on an extended conformation and points away from the hydrogen bonding cavity. Importantly, coordinating interaction is effective in imposing a restrained geometry to this side arm, with the quinoline ring being oriented opposite the complementary nucleobase. Moreover, the coordination-induced activity control can be reversed by supplementation with a number of chelating agents. The concept described is unique in installing an auxiliary side arm with bending flexibility to control oligonucleotide functions. Finally, these findings show promising potential of supramolecular coordination chemistry for DNA epigenetics.