Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1
Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1
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DOI：
10.1158/0008-5472.can-06-3123
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Sowers, Lawrence C.
中科院分区：
文献类型：
--
作者：
Valinluck, Victoria;Sowers, Lawrence C.
胞嘧啶甲基化模式的改变通常在人类肿瘤中观察到。胞嘧啶甲基化模式改变的后果包括转化基因的不适当激活和肿瘤抑制基因的沉默。尽管甲基化变化具有生物学效应，但人们对这种变化是如何引起的知之甚少。胞嘧啶甲基化模式从亲代细胞到子代细胞的遗传能力归因于甲基化敏感的人类维持甲基转移酶DNMT1的保真度，该酶在DNA复制后高特异性地甲基化半甲基化CpG序列的未甲基化链。我们一直在研究可能改变DNMTl特异性的DNA损伤，要么抑制半甲基化位点的甲基化，要么触发先前未甲基化位点的不适当甲基化。在这里，我们展示了已知形式的内源性DNA损伤可以导致高甲基化或低甲基化。炎症诱导的5-卤化胞嘧啶损伤产物，包括5-氯胞嘧啶，模拟5-甲基胞嘧啶并诱导CpG序列中DNMTl的不适当甲基化。相反，5-甲基胞嘧啶的甲基氧化损伤，形成5-羟甲基胞嘧啶，阻止目标胞嘧啶的DNMTI甲基化。我们提出DNA损伤导致的DNMTI选择性降低可能导致胞嘧啶甲基化模式的遗传变化，从而导致人类肿瘤的形成。这些数据可能为炎症和癌症之间的关联提供了一种机制联系。
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 DNMTl, 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 DNMTl methylation within a CpG sequence. In contrast, oxidation damage of the methyl group of 5-methylcytosine, with the formation of 5-hydroxymethylcytosine, prevents DNMTI methylation of the target cytosine. We propose that reduced DNMTI 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.