Linear mitochondrial DNA is rapidly degraded by components of the replication machinery.
Linear mitochondrial DNA is rapidly degraded by components of the replication machinery.
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DOI：
10.1038/s41467-018-04131-w
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发表时间：
2018-04-30
影响因子：
16.6
通讯作者：
Kunz WS
中科院分区：
文献类型：
--
作者：
Peeva V;Blei D;Trombly G;Corsi S;Szukszto MJ;Rebelo-Guiomar P;Gammage PA;Kudin AP;Becker C;Altmüller J;Minczuk M;Zsurka G;Kunz WS
旨在消除线粒体DNA（mtDNA）的致病性突变的新兴基因治疗方法依赖于线性化mtDNA的有效降解，但执行该任务的酶机制目前尚不清楚。在这里，我们表明，在限制性内切酶诱导的mtDNA双链断裂的细胞模型中，线性mtDNA在数小时内被核酸外切活性消除。线粒体5′-3 Mobiexonuclease MGME 1的失活、通过引入p.D274A突变消除线粒体DNA聚合酶POLG的3′-5 Mobiexonuclease活性或敲低线粒体DNA解旋酶TWNK导致线粒体DNA降解严重受阻。我们在灭活其他已知的线粒体核酸酶（EXOG、APEX 2、ENDOG、FEN 1、DNA 2、MRE 11或RBBP 8）时没有观察到类似的效应。我们的数据表明，线性化mtDNA的快速降解是由负责mtDNA复制的相同机制进行的，因此提出了参与酶POLG，TWNK和MGME 1的新作用。为了线粒体基因组的稳定性，需要从细胞中去除受损的线性化mtDNA。在这里，作者阐明了负责快速降解线性DNA的机制的身份，暗示了mtDNA复制因子的作用。
Emerging gene therapy approaches that aim to eliminate pathogenic mutations of mitochondrial DNA (mtDNA) rely on efficient degradation of linearized mtDNA, but the enzymatic machinery performing this task is presently unknown. Here, we show that, in cellular models of restriction endonuclease-induced mtDNA double-strand breaks, linear mtDNA is eliminated within hours by exonucleolytic activities. Inactivation of the mitochondrial 5′-3′exonuclease MGME1, elimination of the 3′-5′exonuclease activity of the mitochondrial DNA polymerase POLG by introducing the p.D274A mutation, or knockdown of the mitochondrial DNA helicase TWNK leads to severe impediment of mtDNA degradation. We do not observe similar effects when inactivating other known mitochondrial nucleases (EXOG, APEX2, ENDOG, FEN1, DNA2, MRE11, or RBBP8). Our data suggest that rapid degradation of linearized mtDNA is performed by the same machinery that is responsible for mtDNA replication, thus proposing novel roles for the participating enzymes POLG, TWNK, and MGME1. Damaged linearized mtDNA needs to be removed from the cell for mitochondrial genome stability. Here the authors shed light into the identity of the machinery responsible for rapidly degrading linearized DNA, implicating the role of mtDNA replication factors.
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影响因子：
4.6
作者：
Schmidt, Tobias;Schmid-Burgk, Jonathan L.;Hornung, Veit
通讯作者：
Hornung, Veit
影响因子：
3.5
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
通讯作者：
Minczuk M
DOI：
10.1016/j.bbadis.2015.05.016
发表时间：
2015-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Shokolenko IN;Alexeyev MF
通讯作者：
Alexeyev MF
影响因子：
11.4
作者：
FOURY, F;VANDERSTRAETEN, S
通讯作者：
VANDERSTRAETEN, S
影响因子：
3.3
作者：
Tadi SK;Sebastian R;Dahal S;Babu RK;Choudhary B;Raghavan SC
通讯作者：
Raghavan SC