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Trapped topoisomerase-DNA covalent complexes in the mitochondria and their role in human diseases
Mitochondrion ( IF 3.9 ) Pub Date : 2021-09-06 , DOI: 10.1016/j.mito.2021.08.017
Benu Brata Das 1 , Arijit Ghosh 1 , Sangheeta Bhattacharjee 1 , Arpan Bhattacharyya 1
Affiliation  

Topoisomerases regulate DNA topology, organization of the intracellular DNA, the transmission of genetic materials, and gene expressions. Other than the nuclear genome, mitochondria also harbor the small, circular DNA (mtDNA) that encodes a critical subset of proteins for the production of cellular ATP; however, mitochondria are solely dependent on the nucleus for all the mitochondrial proteins necessary for mtDNA replication, repair, and maintenance. Mitochondrial genome compiles topological stress from bidirectional transcription and replication, therefore imports four nuclear encoded topoisomerases (Top1mt, Top2α, Top2β, and Top3α) in the mitochondria to relax mtDNA supercoiling generated during these processes. Trapping of topoisomerase on DNA results in the formation of protein-linked DNA adducts (PDAs), which are widely exploited by topoisomerase-targeting anticancer drugs. Intriguingly mtDNA is potentially exposed to DNA damage that has been attributed to a variety of human diseases, including neurodegeneration, cancer, and premature aging. In this review, we focus on the role of different topoisomerases in the mitochondria and our current understanding of the mitochondrial DNA damage through trapped protein-DNA complexes, and the progress in the molecular mechanisms of the repair for trapped topoisomerase covalent complexes (Topcc). Finally, we have discussed how the pathological DNA lesions that cause mtDNA damage, trigger mitochondrial fission and mitophagy, which serve as quality control events for clearing damaged mtDNA.



中文翻译:

线粒体中捕获的拓扑异构酶-DNA共价复合物及其在人类疾病中的作用

拓扑异构酶调节 DNA 拓扑结构、细胞内 DNA 的组织、遗传物质的传递和基因表达。除了核基因组,线粒体还含有小的环状 DNA(mtDNA),它编码用于产生细胞 ATP 的关键蛋白质子集。然而,线粒体完全依赖于细胞核,以获取 mtDNA 复制、修复和维持所必需的所有线粒体蛋白。线粒体基因组编译来自双向转录和复制的拓扑应力,因此在线粒体中导入四种核编码拓扑异构酶(Top1mt、Top2α、Top2β 和 Top3α)以放松在这些过程中产生的 mtDNA 超螺旋。在 DNA 上捕获拓扑异构酶导致形成蛋白质连接的 DNA 加合物 (PDA),被拓扑异构酶靶向的抗癌药物广泛利用。有趣的是,mtDNA 可能会受到 DNA 损伤,这种损伤归因于多种人类疾病,包括神经退化、癌症和过早衰老。在这篇综述中,我们重点关注不同拓扑异构酶在线粒体中的作用,以及我们目前对通过捕获的蛋白质-DNA 复合物造成线粒体 DNA 损伤的理解,以及修复捕获的拓扑异构酶共价复合物 (Topcc) 的分子机制的进展。最后,我们讨论了导致mtDNA损伤的病理性DNA损伤,我们关注不同拓扑异构酶在线粒体中的作用,以及我们目前对通过捕获的蛋白质-DNA 复合物造成线粒体 DNA 损伤的理解,以及修复捕获的拓扑异构酶共价复合物 (Topcc) 的分子机制的进展。最后,我们讨论了导致mtDNA损伤的病理性DNA损伤,我们关注不同拓扑异构酶在线粒体中的作用,以及我们目前对通过捕获的蛋白质-DNA 复合物造成线粒体 DNA 损伤的理解,以及修复捕获的拓扑异构酶共价复合物 (Topcc) 的分子机制的进展。最后,我们讨论了导致mtDNA损伤的病理性DNA损伤, 触发线粒体裂变和线粒体自噬,作为清除受损 mtDNA 的质量控制事件。

更新日期:2021-09-16
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