Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease.
Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease.
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DOI：
10.1093/hmg/ddu336
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发表时间：
2014-12-01
影响因子：
3.5
通讯作者：
Minczuk M
中科院分区：
文献类型：
--
作者：
Nicholls TJ;Zsurka G;Peeva V;Schöler S;Szczesny RJ;Cysewski D;Reyes A;Kornblum C;Sciacco M;Moggio M;Dziembowski A;Kunz WS;Minczuk M
MGME 1，也称为Ddk 1或C20 orf 72，是一种线粒体外切核酸酶，被发现参与复制过程中线粒体DNA（mtDNA）的加工。在这里，我们提出了详细的见解MGME 1在mtDNA的维护中的作用。当MGME 1缺失时，由于5′端的不完全加工，延长的7S DNA种类积累。此外，产生跨越线粒体基因组的整个主弧的11-kb线性mtDNA片段。与对照细胞相比，线性mtDNA分子仅在核酸酶S1处理后才能检测到，11 kb片段在MGME 1缺陷细胞中持续存在。与此同时，我们观察到特征性的mtDNA重复MGME 1的情况下。这些mtDNA重排的断裂点既不对应于经典缺失，也不对应于线性11-kb片段的末端，这一事实表明MGME 1在处理mtDNA末端中的作用，可能使它们能够通过同源重组进行修复。与其功能参与线粒体DNA的维护，我们表明，MGME 1与线粒体复制酶PolgA相互作用，这表明它是线粒体复制体的一个组成部分，它提供了一个额外的核酸外切酶活性。因此，我们的研究结果支持的观点，MGME 1介导的mtDNA加工是必不可少的忠实的线粒体基因组复制，并可能需要mtDNA的分子内重组。
MGME1, also known as Ddk1 or C20orf72, is a mitochondrial exonuclease found to be involved in the processing of mitochondrial DNA (mtDNA) during replication. Here, we present detailed insights on the role of MGME1 in mtDNA maintenance. Upon loss of MGME1, elongated 7S DNA species accumulate owing to incomplete processing of 5′ ends. Moreover, an 11-kb linear mtDNA fragment spanning the entire major arc of the mitochondrial genome is generated. In contrast to control cells, where linear mtDNA molecules are detectable only after nuclease S1 treatment, the 11-kb fragment persists in MGME1-deficient cells. In parallel, we observed characteristic mtDNA duplications in the absence of MGME1. The fact that the breakpoints of these mtDNA rearrangements do not correspond to either classical deletions or the ends of the linear 11-kb fragment points to a role of MGME1 in processing mtDNA ends, possibly enabling their repair by homologous recombination. In agreement with its functional involvement in mtDNA maintenance, we show that MGME1 interacts with the mitochondrial replicase PolgA, suggesting that it is a constituent of the mitochondrial replisome, to which it provides an additional exonuclease activity. Thus, our results support the viewpoint that MGME1-mediated mtDNA processing is essential for faithful mitochondrial genome replication and might be required for intramolecular recombination of mtDNA.
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影响因子：
30.8
作者：
Bourdon, Alice;Minai, Limor;Rotig, Agnes
通讯作者：
Rotig, Agnes
影响因子：
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通讯作者：
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5.6
作者：
BROWN, GG;GADALETA, G;SBISA, E
通讯作者：
SBISA, E