Discovery of a Novel Function for Human Rad51 MAINTENANCE OF THE MITOCHONDRIAL GENOME
Discovery of a Novel Function for Human Rad51 MAINTENANCE OF THE MITOCHONDRIAL GENOME
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DOI：
10.1074/jbc.m109.099846
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发表时间：
2010-06-18
影响因子：
4.8
通讯作者：
Knight, Kendall L.
中科院分区：
文献类型：
--
作者：
Sage, Jay M.;Gildemeister, Otto S.;Knight, Kendall L.
同源重组（HR）在聚合酶复合物遇到阻断DNA损伤时促进复制叉进展中起关键作用，并且它也是DNA双链断裂无错误修复的主要机制。Rad51是所有真核生物中HR的中心催化剂，到目前为止，对人类Rad51的研究只集中在细胞核内发生的事件上。然而，大量的HR蛋白存在于细胞质中，但这些蛋白池的功能尚未得到解决。在这里，我们提供了第一个证明，Rad51和相关的HR蛋白Rad51C和Xrcc 3存在于人类线粒体。我们显示了应激诱导的每种蛋白质的线粒体水平的增加，重要的是，Rad51和线粒体DNA（mtDNA）之间的物理相互作用。Rad51、Rad51C或Xrcc 3的缺失导致mtDNA拷贝数的急剧减少以及特征性氧化应激诱导的拷贝数增加的完全抑制。我们的研究结果确定人mtDNA作为一种新的Rad51底物，并揭示了HR蛋白在维持人线粒体基因组中的重要作用。
Homologous recombination (HR) plays a critical role in facilitating replication fork progression when the polymerase complex encounters a blocking DNA lesion, and it also serves as the primary mechanism for error-free repair of DNA double strand breaks. Rad51 is the central catalyst of HR in all eukaryotes, and to this point studies of human Rad51 have focused exclusively on events occurring within the nucleus. However, substantial amounts of HR proteins exist in the cytoplasm, yet the function of these protein pools has not been addressed. Here, we provide the first demonstration that Rad51 and the related HR proteins Rad51C and Xrcc3 exist in human mitochondria. We show stress-induced increases in both the mitochondrial levels of each protein and, importantly, the physical interaction between Rad51 and mitochondrial DNA (mtDNA). Depletion of Rad51, Rad51C, or Xrcc3 results in a dramatic decrease in mtDNA copy number as well as the complete suppression of a characteristic oxidative stress-induced copy number increase. Our results identify human mtDNA as a novel Rad51 substrate and reveal an important role for HR proteins in the maintenance of the human mitochondrial genome.