Supramolecular Coordination-Directed Reversible Regulation of Protein Activities at Epigenetic DNA Marks.

Authors:
Shao-Ru Wang
Shao-Ru Wang
Wuhan University
China
Jia-qi Wang
Jia-qi Wang
Plastic Surgery Hospital
China
Kun Chen
Kun Chen
Zhejiang University School of Public Health
China
Wei Xiong
Wei Xiong
The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health
China
Lai Wei
Lai Wei
Center for Biostatistics
Philadelphia | United States
Guangyan Qing
Guangyan Qing
Wuhan University of Technology
China
Tian Tian
Tian Tian
Second Affiliated Hospital of Xi'an Jiaotong University
China

J Am Chem Soc 2018 Nov 9;140(46):15842-15849. Epub 2018 Nov 9.

College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education , Wuhan University , Wuhan 430072 , Hubei , China.

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.

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http://dx.doi.org/10.1021/jacs.8b09113DOI Listing
November 2018
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