p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs
p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs
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DOI：
10.1073/pnas.1216922110
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发表时间：
2013-01-02
影响因子：
11.1
通讯作者：
Gudkov, Andrei V.
中科院分区：
文献类型：
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作者：
Leonova, Katerina I.;Brodsky, Leonid;Gudkov, Andrei V.
哺乳动物基因组的大部分是转录失活的，并富含各种类型的散布和串联重复序列。在这里，我们表明，肿瘤抑制蛋白p53与DNA甲基化合作，以保持沉默的大部分小鼠基因组。在p53缺陷型小鼠成纤维细胞中观察到主要类型的短散在核元件（西内斯）B1和B2、由串联重复序列组成的近着丝粒卫星DNA的两条链以及多种非编码RNA的大量转录，但在用DNA去甲基化剂5-氮杂-2 '-脱氧胞苷处理的p53野生型小鼠成纤维细胞中未观察到。这些转录物的丰度超过β-肌动蛋白mRNA的水平150倍以上。这些能够形成双链RNA（dsRNA）的转录物的积累伴随着强烈的内源性诱导I型IFN应答。我们将这种现象命名为“TRAIN”（“重复序列的转录激活干扰素”），在两种癌症易感小鼠模型的自发肿瘤中观察到，这可能反映了癌症中自然发生的DNA低甲基化和p53失活。这些观察结果表明，p53和IFN合作，以防止积累的细胞与激活的重复序列，并提供了一个合理的解释干扰素功能的失调，经常在肿瘤中看到。总体而言，这项工作揭示了p53和IFN的作用，它们是遗传稳定性的关键，因此与肿瘤发生和物种进化相关。
Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes of interspersed and tandem repeats. Here we show that the tumor suppressor protein p53 cooperates with DNA methylation to maintain silencing of a large portion of the mouse genome. Massive transcription of major classes of short, interspersed nuclear elements (SINEs) B1 and B2, both strands of near-centromeric satellite DNAs consisting of tandem repeats, and multiple species of noncoding RNAs was observed in p53-deficient but not in p53 wild-type mouse fibroblasts treated with the DNA demethylating agent 5-aza-2'-deoxycytidine. The abundance of these transcripts exceeded the level of beta-actin mRNA by more than 150-fold. Accumulation of these transcripts, which are capable of forming double-stranded RNA (dsRNA), was accompanied by a strong, endogenous, apoptosis-inducing type I IFN response. This phenomenon, which we named "TRAIN" (for "transcription of repeats activates interferon"), was observed in spontaneous tumors in two models of cancer-prone mice, presumably reflecting naturally occurring DNA hypomethylation and p53 inactivation in cancer. These observations suggest that p53 and IFN cooperate to prevent accumulation of cells with activated repeats and provide a plausible explanation for the deregulation of IFN function frequently seen in tumors. Overall, this work reveals roles for p53 and IFN that are key for genetic stability and therefore relevant to both tumorigenesis and the evolution of species.