Mechanistic Insights on the Inhibition of C5 DNA Methyltransferases by Zebularine

doi:10.1371/journal.pone.0012388

Paper

Mechanistic Insights on the Inhibition of C5 DNA Methyltransferases by Zebularine

Published Aug 24, 2010 · Christine Champion, D. Guianvarc’h, C. Sénamaud-Beaufort

PLoS ONE

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103

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5

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Abstract

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.

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Study Snapshot

Zebularine inhibits DNA methylation by stabilizing DNMT binding to DNA, hindering methylation, and decreasing enzyme dissociation, preventing enzyme turnover at other sites.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Mechanistic Insights on the Inhibition of C5 DNA Methyltransferases by Zebularine

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References

Mutational analysis of the CG recognizing DNA methyltransferase SssI: insight into enzyme-DNA interactions.

The DNA methyltransferase M.SssI plays a crucial role in DNA methylation, with conserved residues S145, R232, and T313 involved in base flipping and mutations affecting DNA binding and methylation activity.

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

Zebularine is a more stable and less cytotoxic DNA methyltransferase inhibitor compared to 5-azacytidine, partly due to differences in stability and reversibility of covalent bonds.

Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells

Zebularine suppresses 5-fluorouracil-induced apoptosis in oral squamous cell carcinoma cells through activation of the cAMP/PKA/CREB pathway, suggesting potential harmful effects in combination therapies.

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DNA methylation patterns in human cells show a relaxed site-specific distribution, with methylation levels of individual cells in one tissue often similar, and allele-specific methylation identified in chromosome 21 gene promoter regions.

Inhibition of cytidine deaminase by zebularine enhances the antineoplastic action of 5-aza-2′-deoxycytidine

Zebularine enhances the antineoplastic action of 5-AZA-CdR by inhibiting cytidine deaminase, suggesting potential for use in combination with 5-AZA-CdR in advanced leukemia patients.

Citations

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