Transcript availability dictates the balance between strand-asynchronous and strand-coupled mitochondrial DNA replication.
Transcript availability dictates the balance between strand-asynchronous and strand-coupled mitochondrial DNA replication.
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DOI：
10.1093/nar/gky852
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发表时间：
2018-11-16
影响因子：
14.9
通讯作者：
Holt IJ
中科院分区：
文献类型：
--
作者：
Cluett TJ;Akman G;Reyes A;Kazak L;Mitchell A;Wood SR;Spinazzola A;Spelbrink JN;Holt IJ
哺乳动物线粒体具有多种DNA复制机制。在许多细胞和组织中，链-异步化机制占主导地位，而不是耦合的领先和滞后链DNA合成。然而，对控制或影响不同复制机制的因素知之甚少，链异步复制需要转录本(又名靴带)的瞬时整合的想法是有争议的。鞋带模型的一个确凿预测是，它依赖于线粒体转录。在这里，我们表明，在人类线粒体中，Twinkle DNA解旋酶的高表达诱导了双向、耦合的领先和滞后链DNA合成，代价是链异步复制；并且这种转换伴随着一些线粒体转录物的稳定水平的下降。然而，在所谓的线粒体DNA的小弧形中，转录水平仍然很高，链异步复制机制是存在的。因此，只有在转录本稀缺的情况下，复制才会切换到链偶联机制，从而在转录本可获得性和复制机制之间建立直接关联。因此，这些发现支持线粒体转录本在线粒体DNA复制的链异步机制中的关键作用；作为推论，线粒体RNA的可用性和RNA/DNA杂交的形成提供了调节细胞器中DNA复制机制的手段。
Mammalian mitochondria operate multiple mechanisms of DNA replication. In many cells and tissues a strand-asynchronous mechanism predominates over coupled leading and lagging-strand DNA synthesis. However, little is known of the factors that control or influence the different mechanisms of replication, and the idea that strand-asynchronous replication entails transient incorporation of transcripts (aka bootlaces) is controversial. A firm prediction of the bootlace model is that it depends on mitochondrial transcripts. Here, we show that elevated expression of Twinkle DNA helicase in human mitochondria induces bidirectional, coupled leading and lagging-strand DNA synthesis, at the expense of strand-asynchronous replication; and this switch is accompanied by decreases in the steady-state level of some mitochondrial transcripts. However, in the so-called minor arc of mitochondrial DNA where transcript levels remain high, the strand-asynchronous replication mechanism is instated. Hence, replication switches to a strand-coupled mechanism only where transcripts are scarce, thereby establishing a direct correlation between transcript availability and the mechanism of replication. Thus, these findings support a critical role of mitochondrial transcripts in the strand-asynchronous mechanism of mitochondrial DNA replication; and, as a corollary, mitochondrial RNA availability and RNA/DNA hybrid formation offer means of regulating the mechanisms of DNA replication in the organelle.
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