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Mechanistic insights on the inhibition of C5 DNA methyltransferases by zebularine

Champion, Christine, Guianvarc'h, Dominique, Sénamaud-Beaufort, Catherine, Jurkowska, Renata Z. ORCID:, Jeltsch, Albert, Ponger, Loïc, Arimondo, Paola B. and Guieysse-Peugeot, Anne-Laure 2010. Mechanistic insights on the inhibition of C5 DNA methyltransferases by zebularine. PLoS ONE 5 (8) , e12388. 10.1371/journal.pone.0012388

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In mammals DNA methylation occurs at position 5 of cytosine in a CpG context and regulates gene expression. It plays an important role in diseases and inhibitors of DNA methyltransferases (DNMTs)—the enzymes responsible for DNA methylation—are used in clinics for cancer therapy. The most potent inhibitors are 5-azacytidine and 5-azadeoxycytidine. Zebularine (1-(β-D-ribofuranosyl)-2(1H)- pyrimidinone) is another cytidine analog described as a potent inhibitor that acts by forming a covalent complex with DNMT when incorporated into DNA. Here we bring additional experiments to explain its mechanism of action. First, we observe an increase in the DNA binding when zebularine is incorporated into the DNA, compared to deoxycytidine and 5-fluorodeoxycytidine, together with a strong decrease in the dissociation rate. Second, we show by denaturing gel analysis that the intermediate covalent complex between the enzyme and the DNA is reversible, differing thus from 5-fluorodeoxycytidine. Third, no methylation reaction occurs when zebularine is present in the DNA. We confirm that zebularine exerts its demethylation activity by stabilizing the binding of DNMTs to DNA, hindering the methylation and decreasing the dissociation, thereby trapping the enzyme and preventing turnover even at other sites.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License
Publisher: Public Library of Science
ISSN: 1932-6203
Date of First Compliant Deposit: 29 March 2021
Last Modified: 06 May 2023 05:30

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