Endogenous Cytosine Damage Products Alter the Site Selectivity of Human DNA Maintenance Methyltransferase DNMT1
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- 1 February 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (3) , 946-950
- https://doi.org/10.1158/0008-5472.can-06-3123
Abstract
Alterations in cytosine methylation patterns are usually observed in human tumors. The consequences of altered cytosine methylation patterns include both inappropriate activation of transforming genes and silencing of tumor suppressor genes. Despite the biological effect of methylation changes, little is known about how such changes are caused. The heritability of cytosine methylation patterns from parent to progeny cells is attributed to the fidelity of the methylation-sensitive human maintenance methyltransferase DNMT1, which methylates with high specificity the unmethylated strand of a hemimethylated CpG sequence following DNA replication. We have been studying DNA damage that might alter the specificity of DNMT1, either inhibiting the methylation of hemimethylated sites or triggering the inappropriate methylation of previously unmethylated sites. Here, we show that known forms of endogenous DNA damage can cause either hypermethylation or hypomethylation. Inflammation-induced 5-halogenated cytosine damage products, including 5-chlorocytosine, mimic 5-methylcytosine and induce inappropriate DNMT1 methylation within a CpG sequence. In contrast, oxidation damage of the methyl group of 5-methylcytosine, with the formation of 5-hydroxymethylcytosine, prevents DNMT1 methylation of the target cytosine. We propose that reduced DNMT1 selectivity resulting from DNA damage could cause heritable changes in cytosine methylation patterns, resulting in human tumor formation. These data may provide a mechanistic link for the associations documented between inflammation and cancer. [Cancer Res 2007;67(3):946–50]Keywords
This publication has 32 references indexed in Scilit:
- Genomic DNA methylation: the mark and its mediatorsPublished by Elsevier ,2006
- Detection of chlorinated DNA and RNA nucleosides by HPLC coupled to tandem mass spectrometry as potential biomarkers of inflammationJournal of Chromatography B, 2005
- Synthesis and Characterization of Oligonucleotides Containing 5-ChlorocytosineChemical Research in Toxicology, 2004
- The history of cancer epigeneticsNature Reviews Cancer, 2004
- Recombinant Human DNA (Cytosine-5) MethyltransferaseJournal of Biological Chemistry, 1999
- Recombinant Human DNA (Cytosine-5) MethyltransferaseJournal of Biological Chemistry, 1999
- Synthesis and Characterization of Isotopically Enriched Pyrimidine Deoxynucleoside Oxidation Damage ProductsChemical Research in Toxicology, 1998
- Hypochlorous Acid-Induced Base Modifications in Isolated Calf Thymus DNAChemical Research in Toxicology, 1997
- DNA adduct 8-hydroxyl-2′-deoxyguanosine (8-hydroxyguanine) affects function of human DNA methyltransferaseCarcinogenesis: Integrative Cancer Research, 1995
- Assessment of chlorination by human neutrophilsNature, 1983