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Title

DNA (Cytosine-C5) methyltransferase inhibition by oligodeoxyribonucleotides containing 2-(1H)-pyrimidinone (zebularine aglycon) at the enzymatic target site

AuthorsVan Bemmel, Dana M.; Brank, Adam S.; Eritja Casadellà, Ramón ; Márquez, Víctor E.; Christman, Judith K.
KeywordsZebularine
DNA methylation
2(1H)-Pyrimidinone riboside
DNA methyltransferase
5-aza-2'-deoxycytidine
Issue Date23-May-2009
PublisherElsevier
CitationBiochemical Pharmacology 78(6): 633-641 (2009)
AbstractAberrant cytosine methylation in promoter regions leads to gene silencing associated with cancer progression. A number of DNA methyltransferase inhibitors are known to reactivate silenced genes; including 5-azacytidine and 2-(1H)-pyrimidinone riboside (zebularine). Zebularine is a more stable, less cytotoxic inhibitor compared to 5-azacytidine. To determine the mechanistic basis for this difference, we carried out a detailed comparisons of the interaction between purified DNA methyltransferases and oligodeoxyribonucleotides (ODNs) containing either 5-azacytosine or 2-(1H)-pyrimidinone in place of the cytosine targeted for methylation. When incorporated into small ODNs, the rate of C5 DNA methyltransferase inhibition by both nucleosides is essentially identical. However, the stability and reversibility of the enzyme complex in the absence and presence of cofactor differs. 5-Azacytosine ODNs form complexes with C5 DNA methyltransferases that are irreversible when the 5-azacytosine ring is intact. ODNs containing 2-(1H)-pyrimidinone at the enzymatic target site are competitive inhibitors of both prokaryotic and mammalian DNA C5 methyltransferases. We determined that the ternary complexes between the enzymes, 2-(1H)-pyrimidinone inhibitor, and the cofactor S-adenosyl methionine are maintained through the formation of a reversible covalent interaction. The differing stability and reversibility of the covalent bonds may partially account for the observed differences in cytotoxicity between zebularine and 5-azacytidine inhibitors.
Description20 pages, 7 figures, 1 table.-- PMID: 19467223 [PubMed].-- PMCID: PMC2756644.-- NIHMSID: NIHMS130041.-- Printed version published Sep 15, 2009.
Publisher version (URL)http://dx.doi.org/10.1016/j.bcp.2009.05.017
URIhttp://hdl.handle.net/10261/28601
DOI10.1016/j.bcp.2009.05.017
ISSN0006-2952
E-ISSN1873-2968
Appears in Collections:(IQAC) Artículos
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