在哺乳动物线粒体中DNA甲基化转移酶,胞嘧啶甲基化,和胞嘧啶羟甲基化.docxVIP

哺乳动物线粒体中DNA甲基化转移酶1，胞嘧啶甲基化和胞嘧啶羟甲基化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 signi ficance 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.线粒体DNA（mtDNA）已经报道在核基因组中CpG二核苷酸上包含5甲基化胞嘧啶（5mC），但是mtDNA甲基化产生的机制和它功能的重要性都还不知道。我们现在报道5hmC5羟甲基化胞嘧啶和5mC一样存在于哺乳动物mtDNA中，表明之前的研究低估了胞嘧啶修饰在基因组中的水平。DNA甲基化转移酶1（DNMT1）转移到线粒体，被一个线粒体靶序列？驱动立刻定位到大家公认的转录起始位点？的上游。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 PGC1α, transcription factors that activate expression of nuclear-encoded mitochondrial genes in response to（响应，反应） hypoxia, and by loss of（失去） 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（好像是，仿佛） responsible for（是的原因，为负责） mtDNA cytosine methylation, from which 5hmC is presumed to be derived, and its expression is controlled by factors that regulate mitochondrial function.这个靶序列在哺乳动物中是保守的，编码的多肽引导一个外源蛋白到线粒体上。DNMT1是三个已知催化活性的DNA甲基化转移酶中唯一一个针对线粒体的。线粒体DNMT1（mtDNMT1）结合mtDNA，证明线粒体基质中存在mtDNMT1。NRF1和PGC1α上调mtDNMT1的表达，转录因子激活核编码线粒体基因的表达是对低氧的反应，失去P53，一个肿瘤抑制因子已知可调节线粒体新陈代谢。改变mtDNMT1表达不对称地影响mtDNA重链和轻链的转