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De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2′-deoxycytidine
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De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2′-deoxycytidine
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De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2′-deoxycytidine
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Journal Article
De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2′-deoxycytidine
2005
Overview
The deoxycytidine analog 5-aza-2′-deoxycitidine (5-aza-dC) is a potent chemotherapeutic agent effective against selective types of cancer. The molecular mechanism by which 5-aza-dC induces cancer cell death, however, is not fully understood. It has been accepted that the mechanism of toxicity is due to the covalent binding between the DNA methyltransferase (Dnmt) and 5-aza-dC-substituted DNA. In order to define which member of the Dnmt family plays a dominant role in the cytotoxicity, we examined the effect of 5-aza-dC on cell growth and apoptosis in various Dnmt null mutant embryonic stem (ES) cells. Of interest, Dnmt3a–Dnmt3b double null ES cells were highly resistant to 5-aza-dC when compared to wild type, Dnmt3a null, Dnmt3b null, or Dnmt1 null ES cells. The cellular sensitivity to 5-aza-dC correlated well with the expression status of Dnmt3 in both undifferentiated and differentiated ES cells. When exogenous Dnmt3a or Dnmt3b was expressed in double null ES cells, the sensitivity to 5-aza-dC was partially restored. These results suggest that the cytotoxic effect of 5-aza-dC may be mediated primarily through Dnmt3a and Dnmt3b
de novo
DNA methyltransferases. Further, the ability to form Dnmt-DNA adducts was similar in Dnmt1 and Dnmt3, and the expression level of Dnmt3 was not higher than that of Dnmt1 in ES cells. Therefore, Dnmt3-DNA adducts may be more effective for inducing apoptosis than Dnmt1-DNA adducts. These results imply a therapeutic potential of 5-aza-dC to cancers expressing Dnmt3.
Publisher
Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
Subject
/ Animals
/ Azacitidine - analogs & derivatives
/ Biological and medical sciences
/ Cancer
/ Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
/ DNA (Cytosine-5-)-Methyltransferase 1
/ DNA (Cytosine-5-)-Methyltransferases - metabolism
/ DNA (Cytosine-5-)-Methyltransferases - physiology
/ DNA Modification Methylases - metabolism
/ Dose-Response Relationship, Drug
/ Embryo, Mammalian - cytology
/ Enzymes
/ Fundamental and applied biological sciences. Psychology
/ Genes
/ Genomes
/ Leukemia
/ Medicine
/ Mice
/ Molecular and cellular biology
/ Mutation
/ Oncology
/ Toxicity
