Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
MinireviewDNA methylation and the association between genetic and epigenetic changes: relation to carcinogenesis
Introduction
DNA can be modified by a variety of damaging agents originating from both exogenous and endogenous sources. Those modifications that are not successfully repaired can generate genomic mutations and result in the expression of proteins showing a spectrum of altered functional properties. In addition, there are heritable changes in chromatin structure and gene expression that do not involve changes in base sequence. Such changes occur by mechanisms that are not completely understood, but most probably include altered patterns of DNA methylation.
Increased methylation of CpG dinucleotides, particularly in the 5′-promoter regions of mammalian genes, involves a DNA-methyltransferase (DNA-MTase) – catalyzed formation of 5-methylcytosine (5MeC) that is generally associated with a decrease in gene expression. Alterations in the DNA methylation profile of mammalian cells are thought to play a central role in tissue-specific gene expression, as well as in physiological processes, such as aging, carcinogenesis, etc. Hypermethylation of tumor suppressor genes and/or hypomethylation of oncogenes are common events in carcinogenesis (see [1]and references therein.) Heritable changes in DNA methylation profile have been designated epimutations by Holliday 2, 3and are referred to here as epigenetic events.
It is the purpose of this paper to present the current status of the evidence linking DNA damage (oxidative lesions, alkylation of bases, formation of abasic sites, etc.) to changes in the DNA methylation profile, including the effect of 5MeC on the repair of DNA damage, to the process of carcinogenesis. Furthermore, both the presence of 5MeC in DNA and catalysis by the enzyme DNA-MTase are by themselves intrinsically mutagenic. In addition, cells from many tumor types have been shown to possess elevated levels of DNA-MTase activity and altered patterns of DNA methylation 3, 4, 5, 6. Finally, chemicals, such as topoisomerase II inhibitors and inhibitors of DNA synthesis, have the ability to induce hypomethylation or hypermethylation of DNA. Thus, genetic and epigenetic changes have profound effects on one another and are thought to play a central role in the process of carcinogenesis.
Section snippets
Role of DNA damage in DNA methylation
DNA lesions, many of which are potentially mutagenic, have been shown to interfere with the ability of DNA to serve as a substrate for DNA-MTases. This can result in a generalized hypomethylation of cytosine residues at CpG sites. Wilson and Jones [7], using a mouse spleen DNA-MTase found that both abasic sites and X-ray-induced single-stranded breaks, reduced the methyl-accepting ability of DNA. In addition, carcinogens like benzo(a)pyrene and ethylnitrosourea have been shown to induce
Oxidative and alkylation damage to DNA
Studies with both the HpaII prokaryotic [11]and the human placental [12]DNA-MTases have shown that the presence of 8-oxo-2′-deoxyguanosine (oxo8dG) in CpCpGpGp sequences, strongly inhibits the methylation of adjacent C residues. It is interesting that the presence of oxo8dG in CpCpGpGp sequences also intereferes with the ability of prokaryotic restriction nucleases to cleave DNA [13]. Oxo8dG, generated by oxidative damage to DNA (hydroxyl radical, singlet oxygen), a potentially mutagenic lesion
Mutational hotspots and DNA-methyltransferases
Studies involving a variety of prokaryotic and eukaryotic DNA-MTases which methylate cytosine at CpG sites have shown that they constitute a family of enzymes containing similar structural motifs [21]. They each possess a cysteine residue at the active site, form a covalent bond with the 6-carbon of cytosine and catalyze the transfer of a methyl group from S-adenosylmethionine (SAM) to the 5-carbon of cytosine.
Methylated CpG sites in DNA represent mutational hotspots. Based upon extrapolations
Chemicals modulating DNA methylation
Many different categories of chemicals can modify DNA methylation, DNA-MTase activity, and the configuration of chromation. However, their precise involvement in differential gene expression, as well as in developmental processes, and the process of carcinogenesis, awaits clarification.
Many chemicals (Table 1), such as topoisomerase II inhibitors, microtubule inhibitors, and inhibitors of DNA synthesis (hydroxyurea, cytosine arabinoside, methotrexate, aphidicolin, etc.), cause DNA
DNA methylation and carcinogenesis
An association between DNA methylation and carcinogenesis was shown by Kautiainen and Jones [4]in 1986, when they found that most tumor cells examined contained from 4- to 3000-fold higher levels of DNA-MTase activity than non-tumorigenic cells. El-Deiry et al. [5]subsequently found that human colorectal adenomas showed a 60- to 200-fold increase in DNA-MTase gene expression, despite a reduced content of genomic 5MeC. The progression of colon cancer appears to correlate with the expression of
Conclusions
A variety of DNA lesions, including those generated by oxidative and alkylation damage, are potentially mutagenic and can also modulate patterns of DNA methylation (epigenetic). Conversely, both 5MeC and the free radical nitric oxide can interfere with the repair of alkylation damage. The presence of 5MeC in DNA and the catalytic activity of the enzyme DNA-MTase are intrinsically mutagenic. Consequently, DNA lesions and methylation patterns have profound effects on one another.
Diverse chemicals
Acknowledgements
The author acknowledges the helpful suggestions of Drs. John W. Drake, Michael D. Shelby and Kenneth R. Tindall of NIEHS, during the preparation of this manuscript.
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