NDLI: Mutagenicity of 5-aza-2′-deoxycytidine is mediated by the mammalian DNA methyltransferase

Content Provider	PubMed Central
Author	Laurie, Jackson-grusby Laird, Peter W. Magge, Suresh N. Moeller, Benjamin J. Jaenisch, Rudolf
Copyright Year	1997
Abstract	The cytosine analog 5-aza-2′-deoxycytidine has been used clinically to reactivate genes silenced by DNA methylation. In particular, patients with β-thalassemia show fetal globin expression after administration of this hypomethylating drug. In addition, silencing of tumor suppressor gene expression by aberrant DNA methylation in tumor cells may potentially be reversed by a similar regimen. Consistent with its function in maintaining tumor suppressor gene expression, 5-aza-2′-deoxycytidine significantly reduces intestinal tumor multiplicity in the predisposed Min mouse strain. Despite its utility as an anti-cancer agent, the drug is highly mutagenic by an unknown mechanism. To gain insight into how 5-aza-2′-deoxycytidine induces mutations in vivo, we examined the mutational spectrum in an Escherichia coli lac I transgene in colonic DNA from 5-aza-2′-deoxycytidine-treated mice. Mutations induced by 5-aza-2′-deoxycytidine were predominantly at CpG dinucleotides, which implicates DNA methyltransferase in the mutagenic mechanism. C:G→G:C transversions were the predominant class of mutations observed. We suggest a model for how the mammalian DNA methyltransferase may be involved in facilitating these mutations. The observation that 5-aza-2′-deoxycytidine-induced mutations are mediated by the enzyme suggests that novel inhibitors of DNA methyltransferase, which can inactivate the enzyme before its interaction with DNA, are needed for chemoprevention or long term therapy.
Starting Page	4681
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	9
Volume Number	94
Language	English
Publisher	The National Academy of Sciences of the USA
Publisher Date	1997-04-29
Access Restriction	Open
Rights Holder	The National Academy of Sciences of the USA
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation.

Mutagenicity of 5-aza-2'-deoxycytidine is mediated by the mammalian DNA methyltransferase.

Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation.

Consequences of combining siRNA-mediated DNA methyltransferase 1 depletion with 5-aza-2′-deoxycytidine in human leukemic KG1 cells

Antineoplastic activity of the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine in anaplastic large cell lymphoma

Epigenetic DNA-(cytosine-5-carbon) modifications: 5-aza-2′-deoxycytidine and DNA-demethylation

Oncogene regulation of tumor suppressor genes in tumorigenesis

Isoform switching and exon skipping induced by the DNA methylation inhibitor 5-Aza-2′-deoxycytidine

Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2'-deoxycytidine.

Mutagenicity of 5-aza-2′-deoxycytidine is mediated by the mammalian DNA methyltransferase

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Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation.

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Mutagenicity of 5-aza-2′-deoxycytidine is mediated by the mammalian DNA methyltransferase