Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters
Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters
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DOI：
10.1073/pnas.0407729102
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发表时间：
2005-01-25
影响因子：
11.1
通讯作者：
Pradhan, S
中科院分区：
文献类型：
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作者：
Estève, PO;Chin, HG;Pradhan, S
DNA (胞嘧啶-5)-甲基转移酶 (DNMT) 1 通过甲基化依赖性和非甲基化依赖性机制参与基因的转录抑制。此处，DNMT1 显示与 p53 结合并在细胞核中共定位。 DNMT1 介导的甲基化在体外受 p53 刺激。 p53 诱导后，含有抗凋亡基因生存素启动子（含有天然 p53 结合位点）的报告构建体在 WT HCT116 细胞中被甲基化，但在 DNMT1 null 或 p53 null 细胞中则不会甲基化。内源性生存素基因抑制涉及 DNMT1 和 p53 之间的合作，并通过引入 DNMT1 或 p53 特异性小抑制性 RNA 来缓解。与亲代细胞相比，DNMT1 缺失细胞对 p53 反应性生存素和 cdc25C 基因表达没有表现出显着的抑制作用。正常人成纤维细胞也表现出类似的 DNMT1 和 p53 介导的生存素启动子甲基化，表明 p53 和 DNMT1 在基因沉默中的合作。
DNA (cytosine-5)-methyltransferase (DNMT) 1 participates in transcriptional repression of genes by methylation-dependent and -independent mechanisms. Here, DNMT1 is shown to bind p53 and colocallize in the nucleus. DNMT1-mediated methylation is stimulated by p53 in vitro. Upon p53 induction, a reporter construct containing the antiapoptotic gene survivin promoter, which contains a natural p53 binding site, was methylated in WT HCT116 cells but not in DNMT1 null or p53 null cells. Endogenous survivin gene repression involves cooperation between DNMT1 and p53 and is relieved by introduction of DNMT1- or p53-specific small inhibitory RNA. DNMT1 null cells did not exhibit a significant repressive effect for p53 responsive survivin and cdc25C gene expression compared with the parental cells. Normal human fibroblasts also exhibited similar DNMT1- and p53-mediated methylation of the survivin promoter, suggesting cooperation between p53 and DNMT1 in gene silencing.