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DNA methylation and the association between genetic and epigenetic changes: relation to carcinogenesis

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Abstract

This paper examines the relationship between DNA mutagenic lesions, DNA methylation and the involvement of these changes in the process of carcinogenesis. Many types of DNA damage (oxidative lesions, alkylation of bases, abasic sites, photodimers, etc.) interfere with the ability of mammalian cell DNA to be methylated at CpG dinucleotides by DNA-methyltransferases (DNA-MTases). This can result in altered patterns in the distribution of 5-methylcytosine (5MeC) residues at CpG sites. Methylation of DNA is an epigenetic change that by definition is heritable, can result in changes in chromatin structure, and is often accompanied by modified patterns of gene expression. The presence of 5MeC in DNA, as well as oxidative stress induced by the free radical nitric oxide, can interefere with the repair of alkylation damage, thereby increasing the level of potentially mutagenic lesions. CpG sites in DNA represent mutational hotspots, with both the presence of 5MeC in DNA and the catalytic activity of DNA-MTases being intrinsically mutagenic. The process of carcinogenesis has frequently been associated with an increased expression of DNA-MTase activity, accompanied by either hypermethylation or hypomethylation of target cell (progenitor tumor cell) DNA. In addition, there is evidence that overexpression of DNA-MTase activity could result in increased cytosine methylation at non-CpG sites. A variety of chemicals can alter the extent of DNA methylation in mammalian cells. These include inhibitors of topoisomerase II, as well as inhibitors of DNA synthesis, microtubule formation, histone deacetylation, transmethylation, etc. Genetic and epigenetic changes in DNA have a profound influence on one another and could play a major role in the process of carcinogenesis, by modulating both the extent and the pattern of gene expression.

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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