Wachsman J T
Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Mutat Res. 1997 Apr 14;375(1):1-8. doi: 10.1016/s0027-5107(97)00003-1.
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.
本文研究了DNA诱变损伤、DNA甲基化以及这些变化在致癌过程中的作用之间的关系。多种类型的DNA损伤（氧化损伤、碱基烷基化、无碱基位点、光二聚体等）会干扰哺乳动物细胞DNA被DNA甲基转移酶（DNA-MTases）在CpG二核苷酸处甲基化的能力。这可能导致CpG位点处5-甲基胞嘧啶（5MeC）残基的分布模式发生改变。DNA甲基化是一种表观遗传变化，从定义上讲是可遗传的，可导致染色质结构改变，并常常伴随着基因表达模式的改变。DNA中5MeC的存在以及自由基一氧化氮诱导的氧化应激，会干扰烷基化损伤的修复，从而增加潜在诱变损伤的水平。DNA中的CpG位点代表突变热点，DNA中5MeC的存在以及DNA-MTases的催化活性本身都具有诱变性。致癌过程常常与DNA-MTase活性的表达增加相关，同时伴随着靶细胞（肿瘤祖细胞）DNA的高甲基化或低甲基化。此外，有证据表明DNA-MTase活性的过表达可能导致非CpG位点处胞嘧啶甲基化增加。多种化学物质可改变哺乳动物细胞中DNA甲基化的程度。这些物质包括拓扑异构酶II抑制剂，以及DNA合成、微管形成、组蛋白去乙酰化、转甲基化等的抑制剂。DNA的遗传和表观遗传变化相互之间具有深远影响，并且可能通过调节基因表达的程度和模式在致癌过程中发挥主要作用。
