DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria
DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria
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DOI：
10.1073/pnas.1012311108
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发表时间：
2011-03-01
影响因子：
11.1
通讯作者：
Taylor, Shirley M.
中科院分区：
文献类型：
--
作者：
Shock, Lisa S.;Thakkar, Prashant V.;Taylor, Shirley M.
据报道，线粒体 DNA (mtDNA) 在 CpG 二核苷酸处含有 5-甲基胞嘧啶 (5mC)，与核基因组中一样，但产生 mtDNA 甲基化的机制及其功能意义尚不清楚。我们现在报告哺乳动物 mtDNA 中存在 5-羟甲基胞嘧啶 (5hmC) 以及 5mC，这表明以前的研究低估了该基因组中胞嘧啶修饰的水平。 DNA 甲基转移酶 1 (DNMT1) 在位于普遍接受的翻译起始位点上游的线粒体靶向序列的驱动下易位至线粒体。该靶向序列在哺乳动物中是保守的，编码的肽将异源蛋白质引导至线粒体。 DNMT1 是三种已知的靶向线粒体的催化活性 DNA 甲基转移酶中唯一的成员。线粒体 DNMT1 (mtDNMT1) 与 mtDNA 结合，证明线粒体基质中存在 mtDNMT1。 mtDNMT1 表达受到 NRF1 和 PGC1 α（在缺氧时激活核编码线粒体基因表达的转录因子）以及 p53（一种已知调节线粒体代谢的肿瘤抑制因子）缺失的影响而上调。 mtDNMT1 表达的改变会不对称地影响 mtDNA 重链和轻链转录本的表达。因此，mtDNMT1 似乎负责 mtDNA 胞嘧啶甲基化，推测 5hmC 源自该甲基化，并且其表达受到调节线粒体功能的因子控制。
Mitochondrial DNA (mtDNA) has been reported to contain 5-methylcytosine (5mC) at CpG dinucleotides, as in the nuclear genome, but neither the mechanism generating mtDNA methylation nor its functional significance is known. We now report the presence of 5-hydroxymethylcytosine (5hmC) as well as 5mC in mammalian mtDNA, suggesting that previous studies underestimated the level of cytosine modification in this genome. DNA methyltransferase 1 (DNMT1) translocates to the mitochondria, driven by a mitochondrial targeting sequence located immediately upstream of the commonly accepted translational start site. This targeting sequence is conserved across mammals, and the encoded peptide directs a heterologous protein to the mitochondria. DNMT1 is the only member of the three known catalytically active DNA methyltransferases targeted to the mitochondrion. Mitochondrial DNMT1 (mtDNMT1) binds to mtDNA, proving the presence of mtDNMT1 in the mitochondrial matrix. mtDNMT1 expression is up-regulated by NRF1 and PGC1 alpha, transcription factors that activate expression of nuclear-encoded mitochondrial genes in response to hypoxia, and by loss of p53, a tumor suppressor known to regulate mitochondrial metabolism. Altered mtDNMT1 expression asymmetrically affects expression of transcripts from the heavy and light strands of mtDNA. Hence, mtDNMT1 appears to be responsible for mtDNA cytosine methylation, from which 5hmC is presumed to be derived, and its expression is controlled by factors that regulate mitochondrial function.