Lee Y W, Broday L, Costa M
Institute of Environmental Medicine, New York University Medical Center, NY 10016, USA.
Mutat Res. 1998 Jul 31;415(3):213-8. doi: 10.1016/s1383-5718(98)00078-3.
Methylation of DNA plays an important role in organizing the genome into transcriptionally active and inactive zones. Nickel compounds cause chromatin condensation and DNA methylation in the transgenic gpt+ Chinese hamster cell line (G12). Here we show that nickel is an inhibitor of cytosine 5-methyltransferase activity in vivo and in vitro. In living cells, this inhibition is transient and following a recovery period after nickel treatment, Mtase activity slightly rebounds. Genomic DNA methylation levels are also somewhat decreased following nickel treatment, but with time, there is an elevation of total DNA methylation above basal levels and before any rebound of methyltransferase activity. These results suggest that nickel exposure can elevate total genomic DNA methylation levels even when DNA methyltransferase activity is depressed. These findings may explain the hypermethylation of senescence and tumor suppressor genes found during nickel carcinogenesis and support the model of a direct effect of Ni2+ on chromatin leading to de novo DNA methylation.
DNA甲基化在将基因组组织成转录活性区和非活性区方面起着重要作用。镍化合物可导致转基因gpt +中国仓鼠细胞系（G12）中的染色质浓缩和DNA甲基化。在此我们表明，镍在体内和体外都是胞嘧啶5 - 甲基转移酶活性的抑制剂。在活细胞中，这种抑制是短暂的，镍处理后的恢复期后，甲基转移酶活性会略有反弹。镍处理后基因组DNA甲基化水平也有所降低，但随着时间的推移，总DNA甲基化水平会升高至基础水平以上且在甲基转移酶活性出现任何反弹之前。这些结果表明，即使DNA甲基转移酶活性受到抑制，镍暴露也可提高总基因组DNA甲基化水平。这些发现可能解释了镍致癌过程中发现的衰老和肿瘤抑制基因的高甲基化现象，并支持Ni2 +对染色质产生直接影响从而导致从头DNA甲基化的模型。
