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Modulation of DNA methylation by cat...

Lee, Won Jun.

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Modulation of DNA methylation by catechol-O-methyltransferase and catechol-containing dietary polyphenols.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Modulation of DNA methylation by catechol-O-methyltransferase and catechol-containing dietary polyphenols./
作者:	Lee, Won Jun.
面頁冊數:	145 p.
附註:	Source: Dissertation Abstracts International, Volume: 66-07, Section: B, page: 3651.
Contained By:	Dissertation Abstracts International66-07B.
標題:	Health Sciences, Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3181963
ISBN:	9780542223136

Modulation of DNA methylation by catechol-O-methyltransferase and catechol-containing dietary polyphenols.
Lee, Won Jun.

Modulation of DNA methylation by catechol-O-methyltransferase and catechol-containing dietary polyphenols. - 145 p.

Source: Dissertation Abstracts International, Volume: 66-07, Section: B, page: 3651.

Thesis (Ph.D.)--University of South Carolina, 2005.

The DNA methyltransferase (DNMT)-mediated methylation of DNA at the C-5 position of cytosine within the CpG dinucleotides represents a basic mechanism for epigenetic control of gene expression and maintenance of genome integrity. In the present study, we examined the modulating effects of catechol-O-methyltransferase (COMT) and S-adenosyl-L-homocysteine (SAH) on DNA methylation catalyzed by prokaryotic M.SssI DNMT and human DNMT1. We found that the presence of COMT (at physiologically-relevant concentrations) enhanced the rate of DNA methylation in vitro catalyzed by M.SssI DNMT and human DNMT1. Transfection of the COMT siRNAs (at 100 nM) into these cells caused &sim;50% reduction of COMT expression, and this reduction of the COMT levels resulted in a decrease of the methylation status of the RARbeta gene (a representative gene) in MCF-7 cells. Kinetic studies showed that SAH strongly and noncompetitively inhibited the methylation of DNA by competing S-adenosyl-L-methionine (SAM) off the DNMT, thus shifting more enzyme molecules to a form that is bound with SAH. Our data showed that the enhancement of DNA methylation by COMT likely is due to the sequestration of SAH by COMT, which reduces the availability of the free SAH for DNMT inhibition.

ISBN: 9780542223136Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Modulation of DNA methylation by catechol-O-methyltransferase and catechol-containing dietary polyphenols.
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245 1 0 $a Modulation of DNA methylation by catechol-O-methyltransferase and catechol-containing dietary polyphenols.
300 $a 145 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-07, Section: B, page: 3651.
500 $a Major Adviser: Bao Ting Zhu.
502 $a Thesis (Ph.D.)--University of South Carolina, 2005.
520 $a The DNA methyltransferase (DNMT)-mediated methylation of DNA at the C-5 position of cytosine within the CpG dinucleotides represents a basic mechanism for epigenetic control of gene expression and maintenance of genome integrity. In the present study, we examined the modulating effects of catechol-O-methyltransferase (COMT) and S-adenosyl-L-homocysteine (SAH) on DNA methylation catalyzed by prokaryotic M.SssI DNMT and human DNMT1. We found that the presence of COMT (at physiologically-relevant concentrations) enhanced the rate of DNA methylation in vitro catalyzed by M.SssI DNMT and human DNMT1. Transfection of the COMT siRNAs (at 100 nM) into these cells caused &sim;50% reduction of COMT expression, and this reduction of the COMT levels resulted in a decrease of the methylation status of the RARbeta gene (a representative gene) in MCF-7 cells. Kinetic studies showed that SAH strongly and noncompetitively inhibited the methylation of DNA by competing S-adenosyl-L-methionine (SAM) off the DNMT, thus shifting more enzyme molecules to a form that is bound with SAH. Our data showed that the enhancement of DNA methylation by COMT likely is due to the sequestration of SAH by COMT, which reduces the availability of the free SAH for DNMT inhibition.
520 $a We also studied the modulating effects of coffee polyphenols, tea catechins and bioflavonoids on the in vitro methylation of synthetic DNA substrates and also on the methylation status of the promoter regions of two representative tumor suppressor genes in cultured cells. Each of the coffee polyphenols, tea catechins (catechin, epicatechin, and [-]-epigallocatechin-3-O-gallate [EGCG]) and bioflavonoids (quercetin, fisetin, and myricetin) inhibited M.SssI DNMT- and DNMT1-mediated DNA methylation in a concentration-dependent manner. Kinetic analysis showed that the mechanism by which this catechol-containing dietary polypbenols inhibited DNA methylation predominantly through a noncompetitive mechanism, and this inhibition was largely due to increased formation of SAH (a potent feedback inhibitor of DNA methylation), resulting from the COMT-mediated O-methylation of these dietary catechols. In comparison, the strong inhibitory effect of EGCG on the DNMT-mediated DNA methylation was independent of its own methylation, and it is largely due to its direct inhibition of the DNMTs. This inhibition is strongly enhanced by Mg2+. Computational modeling studies showed that the gallic acid moiety of EGCG plays a crucial role in its direct inhibitory interaction with the catalytic site of the human DNMT1, and its binding with the enzyme is stabilized by Mg2+, suggesting that the inhibition potency of EGCG for human DNMT1 in the presence of Mg2+ would be markedly enhanced, which is in perfect agreement with our experimental finding.
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791 $a Ph.D.
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