Mitochondrial transcription termination factor 1 directs polar replication fork pausing.
Mitochondrial transcription termination factor 1 directs polar replication fork pausing.
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DOI：
10.1093/nar/gkw302
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发表时间：
2016-07-08
影响因子：
14.9
通讯作者：
Gustafsson CM
中科院分区：
文献类型：
--
作者：
Shi Y;Posse V;Zhu X;Hyvärinen AK;Jacobs HT;Falkenberg M;Gustafsson CM
在核核糖体DNA（rDNA）复制过程中，与转录器的冲突可导致复制叉崩溃和基因组不稳定。为了避免这个问题，复制叉屏障蛋白位于rDNA的下游，在那里阻止在与rDNA转录相反的方向上的复制。在线粒体中具有类似功能的潜在候选者是线粒体转录终止因子1（MTERF 1，也表示为mTERF），其结合到核糖体转录单位的下游序列。以前的研究表明，MTERF1阻止核糖体RNA基因的反义转录，我们在这里显示的过程是独立的转录延伸因子TEFM。重要的是，我们现在证明MTERF1以不同的极性阻止线粒体DNA（mtDNA）复制。这种效应可以通过MTERF1作为定向逆解旋酶，通过线粒体解旋酶TWINKLE阻断mtDNA解旋的能力来解释。这一结论也得到了MTERF1刺激TWINKLE暂停的体内证据的支持。我们的结论是，MTERF1可以直接极性复制叉逮捕哺乳动物线粒体。
During replication of nuclear ribosomal DNA (rDNA), clashes with the transcription apparatus can cause replication fork collapse and genomic instability. To avoid this problem, a replication fork barrier protein is situated downstream of rDNA, there preventing replication in the direction opposite rDNA transcription. A potential candidate for a similar function in mitochondria is the mitochondrial transcription termination factor 1 (MTERF1, also denoted mTERF), which binds to a sequence just downstream of the ribosomal transcription unit. Previous studies have shown that MTERF1 prevents antisense transcription over the ribosomal RNA genes, a process which we here show to be independent of the transcription elongation factor TEFM. Importantly, we now demonstrate that MTERF1 arrests mitochondrial DNA (mtDNA) replication with distinct polarity. The effect is explained by the ability of MTERF1 to act as a directional contrahelicase, blocking mtDNA unwinding by the mitochondrial helicase TWINKLE. This conclusion is also supported by in vivo evidence that MTERF1 stimulates TWINKLE pausing. We conclude that MTERF1 can direct polar replication fork arrest in mammalian mitochondria.