Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):19790-5. doi: 10.1073/pnas.1009814107. Epub 2010 Nov 1.
Human tyrosyl-DNA phosphodiesterase (TDP1) hydrolyzes the phosphodiester bond at a DNA 3'-end linked to a tyrosyl moiety and has been implicated in the repair of topoisomerase I (Top1)-DNA covalent complexes. TDP1 can also hydrolyze other 3'-end DNA alterations including 3'-phosphoglycolate and 3'-abasic sites, and exhibits 3'-nucleosidase activity indicating it may function as a general 3'-end-processing DNA repair enzyme. Here, using laser confocal microscopy, subcellular fractionation and biochemical analyses we demonstrate that a fraction of the TDP1 encoded by the nuclear TDP1 gene localizes to mitochondria. We also show that mitochondrial base excision repair depends on TDP1 activity and provide evidence that TDP1 is required for efficient repair of oxidative damage in mitochondrial DNA. Together, our findings provide evidence for TDP1 as a novel mitochondrial enzyme.
人源酪氨酰-DNA 磷酸二酯酶（TDP1）能够水解与酪氨酰部分相连的 DNA 3'端的磷酸二酯键，并且与拓扑异构酶 I（Top1）-DNA 共价复合物的修复有关。TDP1 还可以水解其他 3'端 DNA 改变，包括 3'-磷酸甘油酸和 3'-脱碱基位点，并表现出 3'-核酸酶活性，表明它可能作为一种通用的 3'端处理 DNA 修复酶发挥作用。在这里，我们使用激光共聚焦显微镜、亚细胞分级分离和生化分析证明，由核 TDP1 基因编码的 TDP1 有一部分定位于线粒体。我们还表明，线粒体碱基切除修复依赖于 TDP1 活性，并提供证据表明 TDP1 是有效修复线粒体 DNA 氧化损伤所必需的。总之，我们的研究结果为 TDP1 作为一种新型的线粒体酶提供了证据。
